PSN1_HUMAN
ID PSN1_HUMAN Reviewed; 467 AA.
AC P49768; B2R6D3; O95465; Q14762; Q15719; Q15720; Q96P33; Q9UIF0;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-1996, sequence version 1.
DT 03-AUG-2022, entry version 246.
DE RecName: Full=Presenilin-1;
DE Short=PS-1;
DE EC=3.4.23.- {ECO:0000269|PubMed:10206644, ECO:0000269|PubMed:10811883, ECO:0000269|PubMed:10899933, ECO:0000269|PubMed:12679784, ECO:0000269|PubMed:15274632, ECO:0000269|PubMed:26280335};
DE AltName: Full=Protein S182;
DE Contains:
DE RecName: Full=Presenilin-1 NTF subunit;
DE Contains:
DE RecName: Full=Presenilin-1 CTF subunit;
DE Contains:
DE RecName: Full=Presenilin-1 CTF12;
DE Short=PS1-CTF12;
GN Name=PSEN1; Synonyms=AD3, PS1, PSNL1;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORMS 1 AND 2), VARIANTS AD3
RP LEU-146; ARG-163; GLU-246 AND VAL-286, AND TISSUE SPECIFICITY.
RC TISSUE=Brain;
RX PubMed=7596406; DOI=10.1038/375754a0;
RA Sherrington R., Rogaev E.I., Liang Y., Rogaeva E.A., Levesque G., Ikeda M.,
RA Chi H., Lin C., Li G., Holman K., Tsuda T., Mar L., Foncin J.-F.,
RA Bruni A.C., Montesi M.P., Sorbi S., Rainero I., Pinessi L., Nee L.,
RA Chumakov I., Pollen D., Brookes A., Sanseau P., Polinsky R.J., Wasco W.,
RA da Silva H.A.R., Haines J.L., Pericak-Vance M.A., Tanzi R.E., Roses A.D.,
RA Fraser P.E., Rommens J.M., St George-Hyslop P.H.;
RT "Cloning of a gene bearing missense mutations in early-onset familial
RT Alzheimer's disease.";
RL Nature 375:754-760(1995).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2 AND 3), AND TISSUE SPECIFICITY.
RC TISSUE=Blood, and Brain;
RX PubMed=8641442; DOI=10.1016/0014-5793(96)00054-3;
RA Sahara N., Yahagi Y., Takagi H., Kondo T., Okochi M., Usami M.,
RA Shirasawa T., Mori H.;
RT "Identification and characterization of presenilin I-467, I-463 and I-
RT 374.";
RL FEBS Lett. 381:7-11(1996).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4).
RA Powell C.S., Gegg M.E., Palmer M.S.;
RT "Human presenilin 1 gene encodes an alternative protein-minilin.";
RL Submitted (AUG-1998) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RA Rowen L., Madan A., Qin S., Abbasi N., Dors M., Ratcliffe A., Madan A.,
RA Dickhoff R., Shaffer T., James R., Lasky S., Hood L.;
RT "Complete sequence of the gene for presenilin 1.";
RL Submitted (NOV-1998) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 5).
RA Kang L., Zhang B., Zhou Y., Peng X., Yuan J., Qiang B.;
RL Submitted (SEP-2001) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
RC TISSUE=Tongue;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=12508121; DOI=10.1038/nature01348;
RA Heilig R., Eckenberg R., Petit J.-L., Fonknechten N., Da Silva C.,
RA Cattolico L., Levy M., Barbe V., De Berardinis V., Ureta-Vidal A.,
RA Pelletier E., Vico V., Anthouard V., Rowen L., Madan A., Qin S., Sun H.,
RA Du H., Pepin K., Artiguenave F., Robert C., Cruaud C., Bruels T.,
RA Jaillon O., Friedlander L., Samson G., Brottier P., Cure S., Segurens B.,
RA Aniere F., Samain S., Crespeau H., Abbasi N., Aiach N., Boscus D.,
RA Dickhoff R., Dors M., Dubois I., Friedman C., Gouyvenoux M., James R.,
RA Madan A., Mairey-Estrada B., Mangenot S., Martins N., Menard M., Oztas S.,
RA Ratcliffe A., Shaffer T., Trask B., Vacherie B., Bellemere C., Belser C.,
RA Besnard-Gonnet M., Bartol-Mavel D., Boutard M., Briez-Silla S.,
RA Combette S., Dufosse-Laurent V., Ferron C., Lechaplais C., Louesse C.,
RA Muselet D., Magdelenat G., Pateau E., Petit E., Sirvain-Trukniewicz P.,
RA Trybou A., Vega-Czarny N., Bataille E., Bluet E., Bordelais I., Dubois M.,
RA Dumont C., Guerin T., Haffray S., Hammadi R., Muanga J., Pellouin V.,
RA Robert D., Wunderle E., Gauguet G., Roy A., Sainte-Marthe L., Verdier J.,
RA Verdier-Discala C., Hillier L.W., Fulton L., McPherson J., Matsuda F.,
RA Wilson R., Scarpelli C., Gyapay G., Wincker P., Saurin W., Quetier F.,
RA Waterston R., Hood L., Weissenbach J.;
RT "The DNA sequence and analysis of human chromosome 14.";
RL Nature 421:601-607(2003).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Skin;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [10]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-113.
RX PubMed=9070286; DOI=10.1006/bbrc.1996.6043;
RA Tsujimura A., Yasojima K., Hashimoto-Gotoh T.;
RT "Cloning of Xenopus presenilin-alpha and -beta cDNAs and their differential
RT expression in oogenesis and embryogenesis.";
RL Biochem. Biophys. Res. Commun. 231:392-396(1997).
RN [11]
RP NUCLEOTIDE SEQUENCE [MRNA] OF 24-32, AND ALTERNATIVE SPLICING (ISOFORMS 6
RP AND 7).
RC TISSUE=Megakaryocyte, and Platelet;
RX PubMed=8804415; DOI=10.1016/0014-5793(96)00845-9;
RA Vidal R., Ghiso J., Wisniewski T., Frangione B.;
RT "Alzheimer's presenilin 1 gene expression in platelets and megakaryocytes.
RT Identification of a novel splice variant.";
RL FEBS Lett. 393:19-23(1996).
RN [12]
RP PROTEIN SEQUENCE OF 36-42; 61-76; 109-129; 217-239; 270-278; 315-320;
RP 345-352 AND 381-395 (ISOFORM 1), IDENTIFICATION BY MASS SPECTROMETRY,
RP IDENTIFICATION IN GAMMA-SECRETASE COMPLEX, FUNCTION, CATALYTIC ACTIVITY,
RP AND SUBCELLULAR LOCATION.
RX PubMed=15274632; DOI=10.1021/bi0494976;
RA Fraering P.C., Ye W., Strub J.-M., Dolios G., LaVoie M.J.,
RA Ostaszewski B.L., van Dorsselaer A., Wang R., Selkoe D.J., Wolfe M.S.;
RT "Purification and characterization of the human gamma-secretase complex.";
RL Biochemistry 43:9774-9789(2004).
RN [13]
RP SUBCELLULAR LOCATION, AND TISSUE SPECIFICITY.
RX PubMed=8574969; DOI=10.1038/nm0296-224;
RA Kovacs D.M., Fausett H.J., Page K.J., Kim T.-W., Moir R.D., Merriam D.E.,
RA Hollister R.D., Hallmark O.G., Mancini R., Felsenstein K.M., Hyman B.T.,
RA Tanzi R.E., Wasco W.;
RT "Alzheimer-associated presenilins 1 and 2: neuronal expression in brain and
RT localization to intracellular membranes in mammalian cells.";
RL Nat. Med. 2:224-229(1996).
RN [14]
RP PROTEOLYTIC PROCESSING.
RX PubMed=9173929; DOI=10.1006/nbdi.1997.0129;
RA Podlisny M.B., Citron M., Amarante P., Sherrington R., Xia W., Zhang J.,
RA Diehl T., Levesque G., Fraser P., Haass C., Koo E.H., Seubert P.,
RA St George-Hyslop P.H., Teplow D.B., Selkoe D.J.;
RT "Presenilin proteins undergo heterogeneous endoproteolysis between Thr291
RT and Ala299 and occur as stable N- and C-terminal fragments in normal and
RT Alzheimer brain tissue.";
RL Neurobiol. Dis. 3:325-337(1997).
RN [15]
RP PHOSPHORYLATION.
RX PubMed=9144240; DOI=10.1073/pnas.94.10.5349;
RA Walter J., Gruenberg J., Capell A., Pesold B., Schindzielorz A., Citron M.,
RA Mendla K., St George-Hyslop P.H., Multhaup G., Selkoe D.J., Haass C.;
RT "Proteolytic processing of the Alzheimer disease-associated presenilin-1
RT generates an in vivo substrate for protein kinase C.";
RL Proc. Natl. Acad. Sci. U.S.A. 94:5349-5354(1997).
RN [16]
RP CASPASE CLEAVAGE SITE, AND MUTAGENESIS OF ASP-345; ASP-373 AND ASP-385.
RX PubMed=9485372; DOI=10.1021/bi972106l;
RA Gruenberg J., Walter J., Loetscher H., Deuschle U., Jacobsen H., Haass C.;
RT "Alzheimer's disease associated presenilin-1 holoprotein and its 18-20 kDa
RT C-terminal fragment are death substrates for proteases of the caspase
RT family.";
RL Biochemistry 37:2263-2270(1998).
RN [17]
RP FUNCTION, INTERACTION WITH CTNNB1, AND SUBCELLULAR LOCATION.
RX PubMed=9738936; DOI=10.1016/s0014-5793(98)00886-2;
RA Murayama M., Tanaka S., Palacino J., Murayama O., Honda T., Sun X.,
RA Yasutake K., Nihonmatsu N., Wolozin B., Takashima A.;
RT "Direct association of presenilin-1 with beta-catenin.";
RL FEBS Lett. 433:73-77(1998).
RN [18]
RP INTERACTION WITH FLNA AND FLNB.
RX PubMed=9437013; DOI=10.1523/jneurosci.18-03-00914.1998;
RA Zhang W., Han S.W., McKeel D.W., Goate A., Wu J.Y.;
RT "Interaction of presenilins with the filamin family of actin-binding
RT proteins.";
RL J. Neurosci. 18:914-922(1998).
RN [19]
RP FUNCTION, MUTAGENESIS OF MET-292, AND PROTEOLYTIC PROCESSING.
RX PubMed=10545183; DOI=10.1021/bi9914210;
RA Steiner H., Romig H., Pesold B., Philipp U., Baader M., Citron M.,
RA Loetscher H., Jacobsen H., Haass C.;
RT "Amyloidogenic function of the Alzheimer's disease-associated presenilin 1
RT in the absence of endoproteolysis.";
RL Biochemistry 38:14600-14605(1999).
RN [20]
RP INTERACTION WITH MTCH1.
RX PubMed=10551805; DOI=10.1074/jbc.274.46.32543;
RA Xu X., Shi Y.-C., Wu X., Gambetti P., Sui D., Cui M.-Z.;
RT "Identification of a novel PSD-95/Dlg/ZO-1 (PDZ)-like protein interacting
RT with the C terminus of presenilin-1.";
RL J. Biol. Chem. 274:32543-32546(1999).
RN [21]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH NOTCH.
RX PubMed=10593990; DOI=10.1074/jbc.274.51.36801;
RA Ray W.J., Yao M., Mumm J., Schroeter E.H., Saftig P., Wolfe M.,
RA Selkoe D.J., Kopan R., Goate A.M.;
RT "Cell surface presenilin-1 participates in the gamma-secretase-like
RT proteolysis of Notch.";
RL J. Biol. Chem. 274:36801-36807(1999).
RN [22]
RP INTERACTION WITH CTNND2 AND CTNNB1, AND SUBCELLULAR LOCATION.
RX PubMed=10037471; DOI=10.1046/j.1471-4159.1999.0720999.x;
RA Levesque G., Yu G., Nishimura M., Zhang D.M., Levesque L., Yu H., Xu D.,
RA Liang Y., Rogaeva E.A., Ikeda M., Duthie M., Murgolo N., Wang L.,
RA VanderVere P., Bayne M.L., Strader C.D., Rommens J.M., Fraser P.E.,
RA St George-Hyslop P.H.;
RT "Presenilins interact with armadillo proteins including neural-specific
RT plakophilin-related protein and beta-catenin.";
RL J. Neurochem. 72:999-1008(1999).
RN [23]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVE SITE, AND MUTAGENESIS OF ASP-257 AND
RP ASP-385.
RX PubMed=10206644; DOI=10.1038/19077;
RA Wolfe M.S., Xia W., Ostaszewski B.L., Diehl T.S., Kimberly W.T.,
RA Selkoe D.J.;
RT "Two transmembrane aspartates in presenilin-1 required for presenilin
RT endoproteolysis and gamma-secretase activity.";
RL Nature 398:513-517(1999).
RN [24]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVE SITE, AND MUTAGENESIS OF ASP-257 AND
RP ASP-385.
RX PubMed=10899933; DOI=10.1046/j.1471-4159.2000.0750583.x;
RA Berezovska O., Jack C., McLean P., Aster J.C., Hicks C., Xia W.,
RA Wolfe M.S., Kimberly W.T., Weinmaster G., Selkoe D.J., Hyman B.T.;
RT "Aspartate mutations in presenilin and gamma-secretase inhibitors both
RT impair notch1 proteolysis and nuclear translocation with relative
RT preservation of notch1 signaling.";
RL J. Neurochem. 75:583-593(2000).
RN [25]
RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF LEU-286.
RX PubMed=10811883; DOI=10.1073/pnas.100049897;
RA Kulic L., Walter J., Multhaup G., Teplow D.B., Baumeister R., Romig H.,
RA Capell A., Steiner H., Haass C.;
RT "Separation of presenilin function in amyloid beta-peptide generation and
RT endoproteolysis of Notch.";
RL Proc. Natl. Acad. Sci. U.S.A. 97:5913-5918(2000).
RN [26]
RP TISSUE SPECIFICITY, AND SUBCELLULAR LOCATION.
RX PubMed=11987239; DOI=10.1006/bcmd.2002.0486;
RA Mirinics Z.K., Calafat J., Udby L., Lovelock J., Kjeldsen L.,
RA Rothermund K., Sisodia S.S., Borregaard N., Corey S.J.;
RT "Identification of the presenilins in hematopoietic cells with localization
RT of presenilin 1 to neutrophil and platelet granules.";
RL Blood Cells Mol. Dis. 28:28-38(2002).
RN [27]
RP FUNCTION, SUBCELLULAR LOCATION, AND IDENTIFICATION IN A COMPLEX WITH CDH1
RP AND CTNNB1.
RX PubMed=11953314; DOI=10.1093/emboj/21.8.1948;
RA Marambaud P., Shioi J., Serban G., Georgakopoulos A., Sarner S., Nagy V.,
RA Baki L., Wen P., Efthimiopoulos S., Shao Z., Wisniewski T., Robakis N.K.;
RT "A presenilin-1/gamma-secretase cleavage releases the E-cadherin
RT intracellular domain and regulates disassembly of adherens junctions.";
RL EMBO J. 21:1948-1956(2002).
RN [28]
RP INTERACTION WITH HERPUD1.
RX PubMed=11799129; DOI=10.1074/jbc.m112372200;
RA Sai X., Kawamura Y., Kokame K., Yamaguchi H., Shiraishi H., Suzuki R.,
RA Suzuki T., Kawaichi M., Miyata T., Kitamura T., De Strooper B.,
RA Yanagisawa K., Komano H.;
RT "Endoplasmic reticulum stress-inducible protein, Herp, enhances presenilin-
RT mediated generation of amyloid beta-protein.";
RL J. Biol. Chem. 277:12915-12920(2002).
RN [29]
RP INTERACTION WITH GFAP, MUTAGENESIS OF 66-ASP--ASP-72; 76-LYS-TYR-77;
RP 82-VAL-ILE-83; VAL-82 AND 84-MET-LEU-85, AND CHARACTERIZATION OF VARIANTS
RP AD3 VAL-79 AND LEU-82.
RX PubMed=12058025; DOI=10.1074/jbc.m112121200;
RA Nielsen A.L., Holm I.E., Johansen M., Bonven B., Jorgensen P.,
RA Jorgensen A.L.;
RT "A new splice variant of glial fibrillary acidic protein GFAPepsilon,
RT interacts with the presenilin proteins.";
RL J. Biol. Chem. 277:29983-29991(2002).
RN [30]
RP INTERACTION WITH CDH2, SUBCELLULAR LOCATION, AND MUTAGENESIS OF ASP-385.
RX PubMed=14515347; DOI=10.1002/jnr.10753;
RA Uemura K., Kitagawa N., Kohno R., Kuzuya A., Kageyama T., Chonabayashi K.,
RA Shibasaki H., Shimohama S.;
RT "Presenilin 1 is involved in maturation and trafficking of N-cadherin to
RT the plasma membrane.";
RL J. Neurosci. Res. 74:184-191(2003).
RN [31]
RP ENZYME ACTIVITY OF A GAMMA-SECRETASE COMPLEX, CATALYTIC ACTIVITY, FUNCTION,
RP AND SUBUNIT.
RX PubMed=12679784; DOI=10.1038/ncb960;
RA Edbauer D., Winkler E., Regula J.T., Pesold B., Steiner H., Haass C.;
RT "Reconstitution of gamma-secretase activity.";
RL Nat. Cell Biol. 5:486-488(2003).
RN [32]
RP COMPONENT OF A GAMMA-SECRETASE COMPLEX WITH PEN2; PSEN1/PSEN2 AND NCSTN.
RX PubMed=12740439; DOI=10.1073/pnas.1037392100;
RA Kimberly W.T., LaVoie M.J., Ostaszewski B.L., Ye W., Wolfe M.S.,
RA Selkoe D.J.;
RT "Gamma-secretase is a membrane protein complex comprised of presenilin,
RT nicastrin, Aph-1, and Pen-2.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:6382-6387(2003).
RN [33]
RP SPLICE ISOFORM(S) THAT ARE POTENTIAL NMD TARGET(S).
RX PubMed=14759258; DOI=10.1186/gb-2004-5-2-r8;
RA Hillman R.T., Green R.E., Brenner S.E.;
RT "An unappreciated role for RNA surveillance.";
RL Genome Biol. 5:R8.1-R8.16(2004).
RN [34]
RP FUNCTION, SUBCELLULAR LOCATION, VARIANT AD3 SER-117, AND CHARACTERIZATION
RP OF VARIANTS AD3 LEU-117 AND SER-117.
RX PubMed=15004326; DOI=10.3233/jad-2004-6105;
RA Dowjat W.K., Kuchna I., Wisniewski T., Wegiel J.;
RT "A novel highly pathogenic Alzheimer presenilin-1 mutation in codon 117
RT (Pro117Ser): Comparison of clinical, neuropathological and cell culture
RT phenotypes of Pro117Leu and Pro117Ser mutations.";
RL J. Alzheimers Dis. 6:31-43(2004).
RN [35]
RP PHOSPHORYLATION AT SER-310 AND SER-346, AND MUTAGENESIS OF SER-310 AND
RP SER-346.
RX PubMed=14576165; DOI=10.1074/jbc.m306653200;
RA Fluhrer R., Friedlein A., Haass C., Walter J.;
RT "Phosphorylation of presenilin 1 at the caspase recognition site regulates
RT its proteolytic processing and the progression of apoptosis.";
RL J. Biol. Chem. 279:1585-1593(2004).
RN [36]
RP TOPOLOGY.
RX PubMed=15385547; DOI=10.1074/jbc.m407898200;
RA Friedmann E., Lemberg M.K., Weihofen A., Dev K.K., Dengler U., Rovelli G.,
RA Martoglio B.;
RT "Consensus analysis of signal peptide peptidase and homologous human
RT aspartic proteases reveals opposite topology of catalytic domains compared
RT with presenilins.";
RL J. Biol. Chem. 279:50790-50798(2004).
RN [37]
RP FUNCTION, ACTIVE SITES ASP-257 AND ASP-385, AND MUTAGENESIS OF TYR-256;
RP ASP-257; ASP-385 AND TYR-389.
RX PubMed=15341515; DOI=10.1111/j.1471-4159.2004.02596.x;
RA Wrigley J.D., Nunn E.J., Nyabi O., Clarke E.E., Hunt P., Nadin A.,
RA De Strooper B., Shearman M.S., Beher D.;
RT "Conserved residues within the putative active site of gamma-secretase
RT differentially influence enzyme activity and inhibitor binding.";
RL J. Neurochem. 90:1312-1320(2004).
RN [38]
RP INTERACTION WITH CDH1 AND CTNNB1.
RX PubMed=16126725; DOI=10.1074/jbc.m507503200;
RA Serban G., Kouchi Z., Baki L., Georgakopoulos A., Litterst C.M., Shioi J.,
RA Robakis N.K.;
RT "Cadherins mediate both the association between PS1 and beta-catenin and
RT the effects of PS1 on beta-catenin stability.";
RL J. Biol. Chem. 280:36007-36012(2005).
RN [39]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-43, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=17081983; DOI=10.1016/j.cell.2006.09.026;
RA Olsen J.V., Blagoev B., Gnad F., Macek B., Kumar C., Mortensen P., Mann M.;
RT "Global, in vivo, and site-specific phosphorylation dynamics in signaling
RT networks.";
RL Cell 127:635-648(2006).
RN [40]
RP FUNCTION, AND CHARACTERIZATION OF VARIANT AD3 VAL-146.
RX PubMed=16959576; DOI=10.1016/j.cell.2006.06.059;
RA Tu H., Nelson O., Bezprozvanny A., Wang Z., Lee S.F., Hao Y.H.,
RA Serneels L., De Strooper B., Yu G., Bezprozvanny I.;
RT "Presenilins form ER Ca2+ leak channels, a function disrupted by familial
RT Alzheimer's disease-linked mutations.";
RL Cell 126:981-993(2006).
RN [41]
RP FUNCTION OF PAL MOTIF, MUTAGENESIS OF PRO-433; ALA-434 AND LEU-435, AND
RP CHARACTERIZATION OF VARIANT AD3 PHE-435.
RX PubMed=16305624; DOI=10.1111/j.1471-4159.2005.03548.x;
RA Wang J., Beher D., Nyborg A.C., Shearman M.S., Golde T.E., Goate A.;
RT "C-terminal PAL motif of presenilin and presenilin homologues required for
RT normal active site conformation.";
RL J. Neurochem. 96:218-227(2006).
RN [42]
RP REVIEW ON VARIANTS.
RX PubMed=8875251; DOI=10.1093/hmg/5.supplement_1.1449;
RA Cruts M., Hendriks L., Van Broeckhoven C.;
RT "The presenilin genes: a new gene family involved in Alzheimer disease
RT pathology.";
RL Hum. Mol. Genet. 5:1449-1455(1996).
RN [43]
RP REVIEW ON VARIANTS.
RX PubMed=9521418;
RX DOI=10.1002/(sici)1098-1004(1998)11:3<183::aid-humu1>3.0.co;2-j;
RA Cruts M., van Broeckhoven C.;
RT "Presenilin mutations in Alzheimer's disease.";
RL Hum. Mutat. 11:183-190(1998).
RN [44]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18691976; DOI=10.1016/j.molcel.2008.07.007;
RA Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R.,
RA Greff Z., Keri G., Stemmann O., Mann M.;
RT "Kinase-selective enrichment enables quantitative phosphoproteomics of the
RT kinome across the cell cycle.";
RL Mol. Cell 31:438-448(2008).
RN [45]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=18669648; DOI=10.1073/pnas.0805139105;
RA Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E.,
RA Elledge S.J., Gygi S.P.;
RT "A quantitative atlas of mitotic phosphorylation.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008).
RN [46]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Leukemic T-cell;
RX PubMed=19690332; DOI=10.1126/scisignal.2000007;
RA Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K.,
RA Rodionov V., Han D.K.;
RT "Quantitative phosphoproteomic analysis of T cell receptor signaling
RT reveals system-wide modulation of protein-protein interactions.";
RL Sci. Signal. 2:RA46-RA46(2009).
RN [47]
RP IDENTIFICATION IN THE GAMMA-SECRETASE COMPLEX, AND INTERACTION WITH CRB2.
RX PubMed=20299451; DOI=10.1074/jbc.m109.038760;
RA Mitsuishi Y., Hasegawa H., Matsuo A., Araki W., Suzuki T., Tagami S.,
RA Okochi M., Takeda M., Roepman R., Nishimura M.;
RT "Human CRB2 inhibits gamma-secretase cleavage of amyloid precursor protein
RT by binding to the presenilin complex.";
RL J. Biol. Chem. 285:14920-14931(2010).
RN [48]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma;
RX PubMed=20068231; DOI=10.1126/scisignal.2000475;
RA Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L.,
RA Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M.;
RT "Quantitative phosphoproteomics reveals widespread full phosphorylation
RT site occupancy during mitosis.";
RL Sci. Signal. 3:RA3-RA3(2010).
RN [49]
RP INVOLVEMENT IN ACNINV3.
RX PubMed=20929727; DOI=10.1126/science.1196284;
RA Wang B., Yang W., Wen W., Sun J., Su B., Liu B., Ma D., Lv D., Wen Y.,
RA Qu T., Chen M., Sun M., Shen Y., Zhang X.;
RT "Gamma-secretase gene mutations in familial acne inversa.";
RL Science 330:1065-1065(2010).
RN [50]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-43 AND SER-367, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21406692; DOI=10.1126/scisignal.2001570;
RA Rigbolt K.T., Prokhorova T.A., Akimov V., Henningsen J., Johansen P.T.,
RA Kratchmarova I., Kassem M., Mann M., Olsen J.V., Blagoev B.;
RT "System-wide temporal characterization of the proteome and phosphoproteome
RT of human embryonic stem cell differentiation.";
RL Sci. Signal. 4:RS3-RS3(2011).
RN [51]
RP SUBCELLULAR LOCATION, AND INTERACTION WITH UBQLN1.
RX PubMed=21143716; DOI=10.1111/j.1600-0854.2010.01149.x;
RA Viswanathan J., Haapasalo A., Bottcher C., Miettinen R., Kurkinen K.M.,
RA Lu A., Thomas A., Maynard C.J., Romano D., Hyman B.T., Berezovska O.,
RA Bertram L., Soininen H., Dantuma N.P., Tanzi R.E., Hiltunen M.;
RT "Alzheimer's disease-associated ubiquilin-1 regulates presenilin-1
RT accumulation and aggresome formation.";
RL Traffic 12:330-348(2011).
RN [52]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-43 AND SER-367, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Cervix carcinoma, and Erythroleukemia;
RX PubMed=23186163; DOI=10.1021/pr300630k;
RA Zhou H., Di Palma S., Preisinger C., Peng M., Polat A.N., Heck A.J.,
RA Mohammed S.;
RT "Toward a comprehensive characterization of a human cancer cell
RT phosphoproteome.";
RL J. Proteome Res. 12:260-271(2013).
RN [53]
RP FUNCTION, INTERACTION WITH APH1A/APH1B AND PEN2, SUBCELLULAR LOCATION, AND
RP CHARACTERIZATION OF VARIANT AD3 ASP-206.
RX PubMed=25394380; DOI=10.1007/s12035-014-8969-1;
RA Chen W.T., Hsieh Y.F., Huang Y.J., Lin C.C., Lin Y.T., Liu Y.C., Lien C.C.,
RA Cheng I.H.;
RT "G206D mutation of presenilin-1 reduces Pen2 interaction, increases
RT Abeta42/Abeta40 ratio and elevates ER Ca(2+) accumulation.";
RL Mol. Neurobiol. 52:1835-1849(2015).
RN [54] {ECO:0007744|PDB:2KR6}
RP STRUCTURE BY NMR OF 292-467.
RA Doetsch V.;
RT "Solution structure of presenilin-1 CTF subunit.";
RL Submitted (DEC-2009) to the PDB data bank.
RN [55]
RP STRUCTURE BY ELECTRON MICROSCOPY (4.5 ANGSTROMS), FUNCTION, SUBCELLULAR
RP LOCATION, SUBUNIT, AND TOPOLOGY.
RX PubMed=25043039; DOI=10.1038/nature13567;
RA Lu P., Bai X.C., Ma D., Xie T., Yan C., Sun L., Yang G., Zhao Y., Zhou R.,
RA Scheres S.H., Shi Y.;
RT "Three-dimensional structure of human gamma-secretase.";
RL Nature 512:166-170(2014).
RN [56] {ECO:0007744|PDB:5FN2, ECO:0007744|PDB:5FN3, ECO:0007744|PDB:5FN4, ECO:0007744|PDB:5FN5}
RP STRUCTURE BY ELECTRON MICROSCOPY (4.00 ANGSTROMS), SUBUNIT, AND TOPOLOGY.
RX PubMed=26623517; DOI=10.7554/elife.11182;
RA Bai X.C., Rajendra E., Yang G., Shi Y., Scheres S.H.;
RT "Sampling the conformational space of the catalytic subunit of human gamma-
RT secretase.";
RL Elife 4:0-0(2015).
RN [57] {ECO:0007744|PDB:5A63}
RP STRUCTURE BY ELECTRON MICROSCOPY (3.40 ANGSTROMS), SUBCELLULAR LOCATION,
RP TOPOLOGY, SUBUNIT, FUNCTION, CATALYTIC ACTIVITY, CHARACTERIZATION OF
RP VARIANTS AD3 LEU-213; ILE-237 AND PHE-261, AND MUTAGENESIS OF ILE-202;
RP LEU-226; LEU-248 AND LEU-424.
RX PubMed=26280335; DOI=10.1038/nature14892;
RA Bai X.C., Yan C., Yang G., Lu P., Ma D., Sun L., Zhou R., Scheres S.H.,
RA Shi Y.;
RT "An atomic structure of human gamma-secretase.";
RL Nature 525:212-217(2015).
RN [58] {ECO:0007744|PDB:4UIS}
RP STRUCTURE BY ELECTRON MICROSCOPY (4.40 ANGSTROMS) OF 81-463, SUBUNIT, AND
RP TOPOLOGY.
RX PubMed=25918421; DOI=10.1073/pnas.1506242112;
RA Sun L., Zhao L., Yang G., Yan C., Zhou R., Zhou X., Xie T., Zhao Y., Wu S.,
RA Li X., Shi Y.;
RT "Structural basis of human gamma-secretase assembly.";
RL Proc. Natl. Acad. Sci. U.S.A. 112:6003-6008(2015).
RN [59]
RP STRUCTURE BY ELECTRON MICROSCOPY (2.70 ANGSTROMS) OF MUTANT ALA-385 IN
RP COMPLEX WITH NOTCH1; PSENEN; APH1A AND NCSTN, SUBUNIT, TOPOLOGY, CATALYTIC
RP ACTIVITY, FUNCTION, ACTIVE SITE, MUTAGENESIS OF GLN-112; 288-TYR--SER-290;
RP 377-ARG--LEU-381; ASP-385; LEU-432 AND 432-LEU--ALA-434, AND DOMAIN.
RX PubMed=30598546; DOI=10.1038/s41586-018-0813-8;
RA Yang G., Zhou R., Zhou Q., Guo X., Yan C., Ke M., Lei J., Shi Y.;
RT "Structural basis of Notch recognition by human gamma-secretase.";
RL Nature 565:192-197(2019).
RN [60]
RP STRUCTURE BY ELECTRON MICROSCOPY (2.60 ANGSTROMS) OF MUTANT ALA-385 IN
RP COMPLEX WITH APP CHAIN C83; PSENEN; APH1A AND NCSTN, SUBUNIT, TOPOLOGY,
RP CATALYTIC ACTIVITY, FUNCTION, ACTIVE SITE, DOMAIN, AND MUTAGENESIS OF
RP GLN-112; 288-TYR--SER-290; 377-ARG--LEU-381; ASP-385; LEU-432 AND
RP 432-LEU--ALA-434.
RX PubMed=30630874; DOI=10.1126/science.aaw0930;
RA Zhou R., Yang G., Guo X., Zhou Q., Lei J., Shi Y.;
RT "Recognition of the amyloid precursor protein by human gamma-secretase.";
RL Science 0:0-0(2019).
RN [61]
RP VARIANTS AD3 THR-143 AND ALA-384.
RX PubMed=8634711; DOI=10.1093/hmg/4.12.2363;
RA Cruts M., Backhovens H., Wang S.-Y., van Gassen G., Theuns J.,
RA de Jonghe C., Wehnert A., de Voecht J., de Winter G., Cras P., Bruyland M.,
RA Datson N., Weissenbach J., den Dunnen J.T., Martin J.-J., Hendriks L.,
RA Van Broeckhoven C.;
RT "Molecular genetic analysis of familial early-onset Alzheimer's disease
RT linked to chromosome 14q24.3.";
RL Hum. Mol. Genet. 4:2363-2372(1995).
RN [62]
RP VARIANTS AD3 LEU-82; HIS-115; THR-139; ARG-163; THR-231; LEU-264; VAL-392
RP AND TYR-410.
RX PubMed=8634712; DOI=10.1093/hmg/4.12.2373;
RA Campion D., Flaman J.-M., Brice A., Hannequin D., Dubois B., Martin C.,
RA Moreau V., Charbonnier F., Didierjean O., Tardieu S., Penet C., Puel M.,
RA Pasquier F., le Doze F., Bellis G., Calenda A., Heilig R., Martinez M.,
RA Mallet J., Bellis M., Clerget-Darpoux F., Agid Y., Frebourg T.;
RT "Mutations of the presenilin I gene in families with early-onset
RT Alzheimer's disease.";
RL Hum. Mol. Genet. 4:2373-2377(1995).
RN [63]
RP VARIANTS AD3 VAL-260; VAL-285 AND VAL-392.
RX PubMed=7651536; DOI=10.1038/376775a0;
RA Rogaev E.I., Sherrington R., Rogaeva E.A., Levesque G., Ikeda M., Liang Y.,
RA Chi H., Lin C., Holman K., Tsuda T., Mar L., Sorbi S., Nacmias B.,
RA Piacentini S., Amaducci L., Chumakov I., Cohen D., Lannfelt L.,
RA Fraser P.E., Rommens J.M., St George-Hyslop P.H.;
RT "Familial Alzheimer's disease in kindreds with missense mutations in a gene
RT on chromosome 1 related to the Alzheimer's disease type 3 gene.";
RL Nature 376:775-778(1995).
RN [64]
RP VARIANTS AD3 VAL-139; VAL-146; TYR-163; SER-267; ALA-280 AND GLY-280.
RX PubMed=7550356; DOI=10.1038/ng1095-219;
RA Clark R.F., Hutton M., Fuldner R.A., Froelich S., Karran E., Talbot C.,
RA Crook R., Lendon C.L., Prihar G., He C., Korenblat K., Martinez A.,
RA Wragg M., Busfield F., Behrens M.I., Myers A., Norton J., Morris J.,
RA Mehta N., Pearson C., Lincoln S., Baker M., Duff K., Zehr C., Perez-Tur J.,
RA Houlden H., Ruiz A., Ossa J., Lopera F., Arcos M., Madrigal L.,
RA Collinge J., Humphreys C., Asworth T., Sarner S., Fox N.C., Harvey R.,
RA Kennedy A., Roques P.K., Cline R.T., Phillips C.A., Venter J.C., Forsel L.,
RA Axelman K., Lilius L., Johnston J., Cowburn R., Viitanen M., Winblad B.,
RA Kosik K.S., Haltia M., Poyhonen M., Dickson D., Mann D., Neary D.,
RA Snowden J., Lantos P., Lannfelt L., Rossor M.N., Roberts G.W., Adams M.D.,
RA Hardy J., Goate A.M.;
RT "The structure of the presenilin 1 (S182) gene and identification of six
RT novel mutations in early onset AD families.";
RL Nat. Genet. 11:219-222(1995).
RN [65]
RP VARIANT AD3 ALA-280, AND INVOLVEMENT IN AD3.
RX PubMed=8837617; DOI=10.1038/nm1096-1146;
RA Lemere C.A., Lopera F., Kosik K.S., Lendon C.L., Ossa J., Saido T.C.,
RA Yamaguchi H., Ruiz A., Martinez A., Madrigal L., Hincapie L., Arango J.C.,
RA Anthony D.C., Koo E.H., Goate A.M., Selkoe D.J., Arango J.C.;
RT "The E280A presenilin 1 Alzheimer mutation produces increased A beta 42
RT deposition and severe cerebellar pathology.";
RL Nat. Med. 2:1146-1150(1996).
RN [66]
RP VARIANTS AD3 PHE-96; ARG-163 AND THR-213.
RX PubMed=8733303; DOI=10.1016/0304-3940(96)12587-8;
RA Kamino K., Sato S., Sakaki Y., Yoshiiwa A., Nishiwaki Y., Takeda H.,
RA Tanabe H., Nishimura T., Li K., St George-Hyslop P.H., Miki T., Ogihara T.;
RT "Three different mutations of presenilin 1 gene in early-onset Alzheimer's
RT disease families.";
RL Neurosci. Lett. 208:195-198(1996).
RN [67]
RP VARIANT AD3 ASP-135.
RX PubMed=9225696; DOI=10.1002/ana.410420121;
RA Crook R., Ellis R., Shanks M., Thal L.J., Perez-Tur J., Baker M.,
RA Hutton M., Haltia T., Hardy J., Galasko D.;
RT "Early-onset Alzheimer's disease with a presenilin-1 mutation at the site
RT corresponding to the Volga German presenilin-2 mutation.";
RL Ann. Neurol. 42:124-128(1997).
RN [68]
RP VARIANT AD3 ALA-280.
RX PubMed=9298817;
RX DOI=10.1002/(sici)1098-1004(1997)10:3<186::aid-humu2>3.0.co;2-h;
RA Lendon C.L., Martinez A., Behrens I.M., Kosik K.S., Madrigal L., Norton J.,
RA Neuman R., Myers A., Busfield F., Wragg M., Arcos M., Arango-Viana J.C.,
RA Ossa J., Ruiz A., Goate A.M., Lopera F.;
RT "E280A PS-1 mutation causes Alzheimer's disease but age of onset is not
RT modified by ApoE alleles.";
RL Hum. Mutat. 10:186-195(1997).
RN [69]
RP VARIANTS AD3 THR-233 AND THR-278.
RX PubMed=9172170; DOI=10.1097/00001756-199704140-00043;
RA Kwok J.B.J., Taddei K., Hallupp M., Fisher C., Brooks W.S., Broe G.A.,
RA Hardy J., Fulham M.J., Nicholson G.A., Stell R., St George-Hyslop P.H.,
RA Fraser P.E., Kakulas B., Clarnette R., Relkin N., Gandy S.E.,
RA Schofield P.R., Martins R.N.;
RT "Two novel (M233T and R278T) presenilin-1 mutations in early-onset
RT Alzheimer's disease pedigrees and preliminary evidence for association of
RT presenilin-1 mutations with a novel phenotype.";
RL NeuroReport 8:1537-1542(1997).
RN [70]
RP VARIANT AD3 PRO-171.
RX PubMed=9833068;
RA Ramirez-Duenas M.G., Rogaeva E.A., Leal C.A., Lin C.,
RA Ramirez-Casillas G.A., Hernandez-Romo J.A., St George-Hyslop P.H.,
RA Cantu J.M.;
RT "A novel Leu171Pro mutation in presenilin-1 gene in a Mexican family with
RT early onset Alzheimer disease.";
RL Ann. Genet. 41:149-153(1998).
RN [71]
RP VARIANT GLY-318.
RX PubMed=9851443; DOI=10.1002/ana.410440617;
RA Mattila K.M., Forsell C., Pirttila T., Rinne J.O., Lehtimaki T., Roytta M.,
RA Lilius L., Eerola A., St George-Hyslop P.H., Frey H., Lannfelt L.;
RT "The Glu318Gly mutation of the presenilin-1 gene does not necessarily cause
RT Alzheimer's disease.";
RL Ann. Neurol. 44:965-967(1998).
RN [72]
RP VARIANT GLY-318.
RX PubMed=9851450; DOI=10.1002/ana.410440624;
RA Aldudo J., Bullido M.J., Frank A., Valdivieso F.;
RT "Missense mutation E318G of the presenilin-1 gene appears to be a
RT nonpathogenic polymorphism.";
RL Ann. Neurol. 44:985-986(1998).
RN [73]
RP VARIANTS AD3 VAL-79; CYS-115 AND VAL-231, AND VARIANT GLY-318.
RX PubMed=9384602; DOI=10.1093/hmg/7.1.43;
RA Cruts M., van Duijn C.M., Backhovens H., van den Broeck M., Wehnert A.,
RA Serneels S., Sherrington R., Hutton M., Hardy J., St George-Hyslop P.H.,
RA Hofman A., van Broeckhoven C.;
RT "Estimation of the genetic contribution of presenilin-1 and -2 mutations in
RT a population-based study of presenile Alzheimer disease.";
RL Hum. Mol. Genet. 7:43-51(1998).
RN [74]
RP VARIANTS AD3 ASP-120; ARG-163; VAL-209; VAL-260; LEU-264; TYR-410 AND
RP PRO-426.
RX PubMed=9521423;
RX DOI=10.1002/(sici)1098-1004(1998)11:3<216::aid-humu6>3.0.co;2-f;
RA Poorkaj P., Sharma V., Anderson L., Nemens E., Alonso M.E., Orr H.,
RA White J., Heston L., Bird T.D., Schellenberg G.D.;
RT "Missense mutations in the chromosome 14 familial Alzheimer's disease
RT presenilin 1 gene.";
RL Hum. Mutat. 11:216-221(1998).
RN [75]
RP VARIANT AD3 GLU-378.
RX PubMed=10200054;
RX DOI=10.1002/(sici)1098-1004(1998)11:6<481::aid-humu13>3.0.co;2-n;
RA Besancon R., Lorenzi A., Cruts M., Radawiec S., Sturtz F., Broussolle E.,
RA Chazot G., van Broeckhoven C., Chamba G., Vandenberghe A.;
RT "Missense mutation in exon 11 (codon 378) of the presenilin-1 gene in a
RT French family with early-onset Alzheimer's disease and transmission study
RT by mismatch enhanced allele specific amplification.";
RL Hum. Mutat. 11:481-481(1998).
RN [76]
RP VARIANT AD3 LYS-139.
RX PubMed=9719376; DOI=10.1136/jmg.35.8.672;
RA Dumanchin C., Brice A., Campion D., Hannequin D., Martin C., Moreau V.,
RA Agid Y., Martinez M., Clerget-Darpoux F., Frebourg T.;
RT "De novo presenilin 1 mutations are rare in clinically sporadic, early
RT onset Alzheimer's disease cases.";
RL J. Med. Genet. 35:672-673(1998).
RN [77]
RP VARIANT AD3 LEU-117.
RX PubMed=9507958; DOI=10.1097/00001756-199801260-00008;
RA Wisniewski T., Dowjat W.K., Buxbaum J.D., Khorkova O., Efthimiopoulos S.,
RA Kulczycki J., Lojkowska W., Wegiel J., Wisniewski H.M., Frangione B.;
RT "A novel Polish presenilin-1 mutation (P117L) is associated with familial
RT Alzheimer's disease and leads to death as early as the age of 28 years.";
RL NeuroReport 9:217-221(1998).
RN [78]
RP VARIANTS AD3 LEU-169 AND GLN-436.
RX PubMed=9831473; DOI=10.1097/00001756-199810050-00034;
RA Taddei K., Kwok J.B., Kril J.J., Halliday G.M., Creasey H., Hallupp M.,
RA Fisher C., Brooks W.S., Chung C., Andrews C., Masters C.L., Schofield P.R.,
RA Martins R.N.;
RT "Two novel presenilin-1 mutations (Ser169Leu and Pro436Gln) associated with
RT very early onset Alzheimer's disease.";
RL NeuroReport 9:3335-3339(1998).
RN [79]
RP VARIANT GLY-318.
RX PubMed=9915968; DOI=10.1086/302200;
RA Dermaut B., Cruts M., Slooter A.J.C., van Gestel S., de Jonghe C.,
RA Vanderstichele H., Vanmechelen E., Breteler M.M., Hofman A.,
RA van Duijn C.M., van Broeckhoven C.;
RT "The Glu318Gly substitution in presenilin 1 is not causally related to
RT Alzheimer disease.";
RL Am. J. Hum. Genet. 64:290-292(1999).
RN [80]
RP VARIANTS AD3 LEU-82; HIS-115; ASP-120; THR-139; LEU-146; ILE-147; ARG-163;
RP CYS-165; TRP-173; THR-231; THR-233; PRO-235; LEU-264; ILE-390; VAL-392 AND
RP TYR-410, AND VARIANT GLY-318.
RX PubMed=10441572; DOI=10.1086/302553;
RA Campion D., Dumanchin C., Hannequin D., Dubois B., Belliard S., Puel M.,
RA Thomas-Anterion C., Michon A., Martin C., Charbonnier F., Raux G.,
RA Camuzat A., Penet C., Mesnage V., Martinez M., Clerget-Darpoux F.,
RA Brice A., Frebourg T.;
RT "Early-onset autosomal dominant Alzheimer disease: prevalence, genetic
RT heterogeneity, and mutation spectrum.";
RL Am. J. Hum. Genet. 65:664-670(1999).
RN [81]
RP VARIANTS AD3 PHE-143 AND SER-436.
RX PubMed=10090481;
RX DOI=10.1002/(sici)1098-1004(1999)13:3<256::aid-humu11>3.0.co;2-p;
RA Palmer M.S., Beck J.A., Campbell T.A., Humphries C.B., Roques P.K.,
RA Fox N.C., Harvey R., Rossor M.N., Collinge J.;
RT "Pathogenic presenilin 1 mutations (P436S and I143F) in early-onset
RT Alzheimer's disease in the UK.";
RL Hum. Mutat. 13:256-256(1999).
RN [82]
RP VARIANT AD3 ARG-209.
RX PubMed=10447269;
RX DOI=10.1002/(sici)1098-1004(1999)14:1<90::aid-humu19>3.0.co;2-s;
RA Sugiyama N., Suzuki K., Matsumura T., Kawanishi C., Onishi H., Yamada Y.,
RA Iseki E., Kosaka K.;
RT "A novel missense mutation (G209R) in exon 8 of the presenilin 1 gene in a
RT Japanese family with presenile familial Alzheimer's disease.";
RL Hum. Mutat. 14:90-90(1999).
RN [83]
RP VARIANTS AD3 LEU-233; ARG-282 AND THR-409, AND VARIANT GLY-318.
RX PubMed=10533070;
RX DOI=10.1002/(sici)1098-1004(199911)14:5<433::aid-humu10>3.0.co;2-k;
RA Aldudo J., Bullido M.J., Valdivieso F.;
RT "DGGE method for the mutational analysis of the coding and proximal
RT promoter regions of the Alzheimer's disease presenilin-1 gene: two novel
RT mutations.";
RL Hum. Mutat. 14:433-439(1999).
RN [84]
RP VARIANT AD3 PRO-169.
RX PubMed=10025789; DOI=10.1212/wnl.52.3.566;
RA Ezquerra M., Carnero C., Blesa R., Gelpi J.L., Ballesta F., Oliva R.;
RT "A presenilin 1 mutation (Ser169Pro) associated with early-onset AD and
RT myoclonic seizures.";
RL Neurology 52:566-570(1999).
RN [85]
RP VARIANT AD3 PRO-219.
RX PubMed=10208579; DOI=10.1097/00001756-199902250-00011;
RA Smith M.J., Gardner R.J., Knight M.A., Forrest S.M., Beyreuther K.,
RA Storey E., McLean C.A., Cotton R.G., Cappal R., Masters C.L.;
RT "Early-onset Alzheimer's disease caused by a novel mutation at codon 219 of
RT the presenilin-1 gene.";
RL NeuroReport 10:503-507(1999).
RN [86]
RP VARIANT AD3 ASN-116.
RX PubMed=10439444; DOI=10.1097/00001756-199908020-00006;
RA Romero I., Joergensen P., Bolwig G., Fraser P.E., Rogaeva E., Mann D.,
RA Havsager A.-M., Joergensen A.L.;
RT "A presenilin-1 Thr116Asn substitution in a family with early-onset
RT Alzheimer's disease.";
RL NeuroReport 10:2255-2260(1999).
RN [87]
RP VARIANTS AD3 VAL-79; LEU-105 AND VAL-139, AND VARIANT GLY-318.
RX PubMed=10631141; DOI=10.1086/302702;
RA Finckh U., Mueller-Thomsen T., Mann U., Eggers C., Marksteiner J.,
RA Meins W., Binetti G., Alberici A., Hock C., Nitsch R.M., Gal A.;
RT "High prevalence of pathogenic mutations in patients with early-onset
RT dementia detected by sequence analyses of four different genes.";
RL Am. J. Hum. Genet. 66:110-117(2000).
RN [88]
RP VARIANT AD3 SER-405.
RX PubMed=10644793; DOI=10.1136/jnnp.68.2.220;
RA Yasuda M., Maeda S., Kawamata T., Tamaoka A., Yamamoto Y., Kuroda S.,
RA Maeda K., Tanaka C.;
RT "Novel presenilin-1 mutation with widespread cortical amyloid deposition
RT but limited cerebral amyloid angiopathy.";
RL J. Neurol. Neurosurg. Psych. 68:220-223(2000).
RN [89]
RP VARIANT AD3 SER-92.
RX PubMed=11027672; DOI=10.1006/bbrc.2000.3646;
RA Lewis P.A., Perez-Tur J., Golde T.E., Hardy J.;
RT "The presenilin 1 C92S mutation increases abeta 42 production.";
RL Biochem. Biophys. Res. Commun. 277:261-263(2000).
RN [90]
RP VARIANT FRONTOTEMPORAL DEMENTIA PRO-113.
RX PubMed=11094121; DOI=10.1212/wnl.55.10.1577;
RA Raux G., Gantier R., Thomas-Anterion C., Boulliat J., Verpillat P.,
RA Hannequin D., Brice A., Frebourg T., Campion D.;
RT "Dementia with prominent frontotemporal features associated with L113P
RT presenilin 1 mutation.";
RL Neurology 55:1577-1578(2000).
RN [91]
RP VARIANTS AD3 MET-94; THR-143 AND ALA-280, AND VARIANT GLY-318.
RX PubMed=11568920;
RX DOI=10.1002/1096-8628(20011001)103:2<138::aid-ajmg1529>3.0.co;2-8;
RA Arango D., Cruts M., Torres O., Backhovens H., Serrano M.L., Villareal E.,
RA Montanes P., Matallana D., Cano C., Van Broeckhoven C., Jacquier M.;
RT "Systematic genetic study of Alzheimer disease in Latin America: mutation
RT frequencies of the amyloid beta precursor protein and presenilin genes in
RT Colombia.";
RL Am. J. Med. Genet. 103:138-143(2001).
RN [92]
RP VARIANT AD3 VAL-282, AND CHARACTERIZATION OF VARIANT AD3 VAL-282.
RX PubMed=11701593; DOI=10.1093/brain/124.12.2383;
RA Dermaut B., Kumar-Singh S., De Jonghe C., Cruts M., Loefgren A., Luebke U.,
RA Cras P., Dom R., De Deyn P.P., Martin J.J., Van Broeckhoven C.;
RT "Cerebral amyloid angiopathy is a pathogenic lesion in Alzheimer's disease
RT due to a novel presenilin 1 mutation.";
RL Brain 124:2383-2392(2001).
RN [93]
RP ERRATUM OF PUBMED:11701593, AND VARIANT AD3 GLU-431.
RA Ringman J.M., Jain V., Murrell J., Ghetti B., Cochran E.J.;
RL Hum. Genet. 109:242-242(2001).
RN [94]
RP VARIANT AD3 ALA-206.
RX PubMed=11710891; DOI=10.1001/jama.286.18.2257;
RA Athan E.S., Williamson J., Ciappa A., Santana V., Romas S.N., Lee J.H.,
RA Rondon H., Lantigua R.A., Medrano M., Torres M., Arawaka S., Rogaeva E.,
RA Song Y.-Q., Sato C., Kawarai T., Fafel K.C., Boss M.A., Seltzer W.K.,
RA Stern Y., St George-Hyslop P.H., Tycko B., Mayeux R.;
RT "A founder mutation in presenilin 1 causing early-onset Alzheimer disease
RT in unrelated Caribbean Hispanic families.";
RL JAMA 286:2257-2263(2001).
RN [95]
RP VARIANT AD3 ILE-237.
RX PubMed=11561050; DOI=10.1136/jnnp.71.4.556;
RA Sodeyama N., Iwata T., Ishikawa K., Mizusawa H., Yamada M., Itoh Y.,
RA Otomo E., Matsushita M., Komatsuzaki Y.;
RT "Very early onset Alzheimer's disease with spastic paraparesis associated
RT with a novel presenilin 1 mutation (Phe237Ile).";
RL J. Neurol. Neurosurg. Psych. 71:556-557(2001).
RN [96]
RP VARIANTS AD3 GLN-35; VAL-79; CYS-115; ASN-116; THR-143; ILE-146; LEU-146;
RP VAL-146; TYR-156 DELINS PHE-THR-TYR; ARG-163; LEU-177; SER-177; PRO-178;
RP ALA-206; SER-206; GLU-209; LEU-213; ARG-222; THR-231; LEU-233; PRO-235;
RP PHE-261; ARG-274; ARG-352 INS; ILE-354; GLN-358; TYR-365; VAL-394; PHE-418;
RP GLU-431; PHE-435 AND VAL-439, AND VARIANT GLY-318.
RX PubMed=11524469; DOI=10.1212/wnl.57.4.621;
RA Rogaeva E.A., Fafel K.C., Song Y.Q., Medeiros H., Sato C., Liang Y.,
RA Richard E., Rogaev E.I., Frommelt P., Sadovnick A.D., Meschino W.,
RA Rockwood K., Boss M.A., Mayeux R., St George-Hyslop P.;
RT "Screening for PS1 mutations in a referral-based series of AD cases: 21
RT novel mutations.";
RL Neurology 57:621-625(2001).
RN [97]
RP VARIANT AD3 SER-266.
RX PubMed=11920851; DOI=10.1002/ajmg.10250;
RA Matsubara-Tsutsui M., Yasuda M., Yamagata H., Nomura T., Taguchi K.,
RA Kohara K., Miyoshi K., Miki T.;
RT "Molecular evidence of presenilin 1 mutation in familial early onset
RT dementia.";
RL Am. J. Med. Genet. 114:292-298(2002).
RN [98]
RP VARIANT AD3 LEU-89.
RX PubMed=11796781; DOI=10.1136/jnnp.72.2.266;
RA Queralt R., Ezquerra M., Lleo A., Castellvi M., Gelpi J., Ferrer I.,
RA Acarin N., Pasarin L., Blesa R., Oliva R.;
RT "A novel mutation (V89L) in the presenilin 1 gene in a family with early
RT onset Alzheimer's disease and marked behavioural disturbances.";
RL J. Neurol. Neurosurg. Psych. 72:266-269(2002).
RN [99]
RP VARIANT AD3 GLY-280.
RX PubMed=12370477; DOI=10.1212/wnl.59.7.1108;
RA O'Riordan S., McMonagle P., Janssen J.C., Fox N.C., Farrell M.,
RA Collinge J., Rossor M.N., Hutchinson M.;
RT "Presenilin-1 mutation (E280G), spastic paraparesis, and cranial MRI white-
RT matter abnormalities.";
RL Neurology 59:1108-1110(2002).
RN [100]
RP VARIANT AD3 PRO-166.
RX PubMed=12048239; DOI=10.1073/pnas.112686799;
RA Moehlmann T., Winkler E., Xia X., Edbauer D., Murrell J., Capell A.,
RA Kaether C., Zheng H., Ghetti B., Haass C., Steiner H.;
RT "Presenilin-1 mutations of leucine 166 equally affect the generation of the
RT Notch and APP intracellular domains independent of their effect on Abeta 42
RT production.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:8025-8030(2002).
RN [101]
RP VARIANT AD3 MET-174.
RX PubMed=12484344; DOI=10.1007/s10048-002-0136-6;
RA Bertoli-Avella A.M., Marcheco Teruel B., Llibre Rodriguez J.J.,
RA Gomez Viera N., Borrajero-Martinez I., Severijnen E.A., Joosse M.,
RA van Duijn C.M., Heredero Baute L., Heutink P.;
RT "A novel presenilin 1 mutation (L174 M) in a large Cuban family with early
RT onset Alzheimer disease.";
RL Neurogenetics 4:97-104(2002).
RN [102]
RP VARIANT AD3 VAL-271.
RX PubMed=12493737; DOI=10.1074/jbc.m211827200;
RA Kwok J.B.J., Halliday G.M., Brooks W.S., Dolios G., Laudon H., Murayama O.,
RA Hallupp M., Badenhop R.F., Vickers J., Wang R., Naslund J., Takashima A.,
RA Gandy S.E., Schofield P.R.;
RT "Presenilin-1 mutation L271V results in altered exon 8 splicing and
RT Alzheimer's disease with non-cored plaques and no neuritic dystrophy.";
RL J. Biol. Chem. 278:6748-6754(2003).
RN [103]
RP VARIANTS AD3 CYS-115; ILE-146; VAL-153; CYS-154; ILE-168 DEL; PRO-171;
RP ASP-184; PHE-229; VAL-235; LEU-237; VAL-260; PHE-263; HIS-269; MET-377 AND
RP VAL-378, AND VARIANT GLY-318.
RX PubMed=12552037; DOI=10.1212/01.wnl.0000042088.22694.e3;
RA Janssen J.C., Beck J.A., Campbell T.A., Dickinson A., Fox N.C.,
RA Harvey R.J., Houlden H., Rossor M.N., Collinge J.;
RT "Early onset familial Alzheimer's disease: Mutation frequency in 31
RT families.";
RL Neurology 60:235-239(2003).
RN [104]
RP VARIANT PIDB VAL-183, CHARACTERIZATION OF VARIANTS AD3 THR-143 AND VAL-282,
RP AND CHARACTERIZATION OF VARIANT PIDB VAL-183.
RX PubMed=15122701; DOI=10.1002/ana.20083;
RA Dermaut B., Kumar-Singh S., Engelborghs S., Theuns J., Rademakers R.,
RA Saerens J., Pickut B.A., Peeters K., van den Broeck M., Vennekens K.,
RA Claes S., Cruts M., Cras P., Martin J.J., Van Broeckhoven C., De Deyn P.P.;
RT "A novel presenilin 1 mutation associated with Pick's disease but not beta-
RT amyloid plaques.";
RL Ann. Neurol. 55:617-626(2004).
RN [105]
RP VARIANT AD3 PRO-85, AND CHARACTERIZATION OF VARIANT AD3 PRO-85.
RX PubMed=15534188; DOI=10.1001/archneur.61.11.1773;
RA Ataka S., Tomiyama T., Takuma H., Yamashita T., Shimada H., Tsutada T.,
RA Kawabata K., Mori H., Miki T.;
RT "A novel presenilin-1 mutation (Leu85Pro) in early-onset Alzheimer disease
RT with spastic paraparesis.";
RL Arch. Neurol. 61:1773-1776(2004).
RN [106]
RP VARIANT AD3 ILE-278.
RX PubMed=15534260; DOI=10.1212/01.wnl.0000143060.98164.1a;
RA Godbolt A.K., Beck J.A., Collinge J., Garrard P., Warren J.D., Fox N.C.,
RA Rossor M.N.;
RT "A presenilin 1 R278I mutation presenting with language impairment.";
RL Neurology 63:1702-1704(2004).
RN [107]
RP VARIANT AD3 ASN-154.
RX PubMed=15364419; DOI=10.1016/j.neulet.2004.07.057;
RA Hattori S., Sakuma K., Wakutani Y., Wada K., Shimoda M., Urakami K.,
RA Kowa H., Nakashima K.;
RT "A novel presenilin 1 mutation (Y154N) in a patient with early onset
RT Alzheimer's disease with spastic paraparesis.";
RL Neurosci. Lett. 368:319-322(2004).
RN [108]
RP VARIANT AD3 PHE-170.
RX PubMed=16344340; DOI=10.1001/archneur.62.12.1821;
RA Snider B.J., Norton J., Coats M.A., Chakraverty S., Hou C.E., Jervis R.,
RA Lendon C.L., Goate A.M., McKeel D.W. Jr., Morris J.C.;
RT "Novel presenilin 1 mutation (S170F) causing Alzheimer disease with Lewy
RT bodies in the third decade of life.";
RL Arch. Neurol. 62:1821-1830(2005).
RN [109]
RP VARIANT AD3 LEU-97.
RX PubMed=15851849; DOI=10.3233/jad-2005-7204;
RA Jia J., Xu E., Shao Y., Jia J., Sun Y., Li D.;
RT "One novel presenilin-1 gene mutation in a Chinese pedigree of familial
RT Alzheimer's disease.";
RL J. Alzheimers Dis. 7:119-124(2005).
RN [110]
RP VARIANT CMD1U GLY-333.
RX PubMed=17186461; DOI=10.1086/509900;
RA Li D., Parks S.B., Kushner J.D., Nauman D., Burgess D., Ludwigsen S.,
RA Partain J., Nixon R.R., Allen C.N., Irwin R.P., Jakobs P.M., Litt M.,
RA Hershberger R.E.;
RT "Mutations of presenilin genes in dilated cardiomyopathy and heart
RT failure.";
RL Am. J. Hum. Genet. 79:1030-1039(2006).
RN [111]
RP CHARACTERIZATION OF VARIANTS AD3 VAL-79; THR-143; VAL-231; PHE-262;
RP PHE-263; VAL-282 AND ALA-384.
RX PubMed=16752394; DOI=10.1002/humu.20336;
RA Kumar-Singh S., Theuns J., Van Broeck B., Pirici D., Vennekens K.,
RA Corsmit E., Cruts M., Dermaut B., Wang R., Van Broeckhoven C.;
RT "Mean age-of-onset of familial alzheimer disease caused by presenilin
RT mutations correlates with both increased Abeta42 and decreased Abeta40.";
RL Hum. Mutat. 27:686-695(2006).
RN [112]
RP VARIANT AD3 GLU-431.
RX PubMed=16628450; DOI=10.1007/s10048-006-0043-3;
RA Yescas P., Huertas-Vazquez A., Villarreal-Molina M.T., Rasmussen A.,
RA Tusie-Luna M.T., Lopez M., Canizales-Quinteros S., Alonso M.E.;
RT "Founder effect for the Ala431Glu mutation of the presenilin 1 gene causing
RT early-onset Alzheimer's disease in Mexican families.";
RL Neurogenetics 7:195-200(2006).
RN [113]
RP VARIANT AD3 GLU-431.
RX PubMed=16897084; DOI=10.1007/s10048-006-0053-1;
RA Murrell J., Ghetti B., Cochran E., Macias-Islas M.A., Medina L.,
RA Varpetian A., Cummings J.L., Mendez M.F., Kawas C., Chui H., Ringman J.M.;
RT "The A431E mutation in PSEN1 causing familial Alzheimer's disease
RT originating in Jalisco State, Mexico: an additional fifteen families.";
RL Neurogenetics 7:277-279(2006).
RN [114]
RP VARIANT AD3 VAL-79, AND CHARACTERIZATION OF VARIANT AD3 VAL-79.
RX PubMed=17366635; DOI=10.1002/ana.21099;
RA Kauwe J.S., Jacquart S., Chakraverty S., Wang J., Mayo K., Fagan A.M.,
RA Holtzman D.M., Morris J.C., Goate A.M.;
RT "Extreme cerebrospinal fluid amyloid beta levels identify family with late-
RT onset Alzheimer's disease presenilin 1 mutation.";
RL Ann. Neurol. 61:446-453(2007).
RN [115]
RP VARIANT AD3 PHE-170.
RX PubMed=17502474; DOI=10.1001/archneur.64.5.738;
RA Piccini A., Zanusso G., Borghi R., Noviello C., Monaco S., Russo R.,
RA Damonte G., Armirotti A., Gelati M., Giordano R., Zambenedetti P.,
RA Russo C., Ghetti B., Tabaton M.;
RT "Association of a presenilin 1 S170F mutation with a novel Alzheimer
RT disease molecular phenotype.";
RL Arch. Neurol. 64:738-745(2007).
RN [116]
RP CHARACTERIZATION OF VARIANTS AD3 LEU-117; LEU-146; GLU-246; VAL-260;
RP LEU-264 AND GLY-280, FUNCTION, AND MUTAGENESIS OF ASP-257.
RX PubMed=17428795; DOI=10.1074/jbc.m611449200;
RA Litterst C., Georgakopoulos A., Shioi J., Ghersi E., Wisniewski T.,
RA Wang R., Ludwig A., Robakis N.K.;
RT "Ligand binding and calcium influx induce distinct ectodomain/gamma-
RT secretase-processing pathways of EphB2 receptor.";
RL J. Biol. Chem. 282:16155-16163(2007).
RN [117]
RP VARIANT GLY-318.
RX PubMed=18485326; DOI=10.1016/j.ajhg.2008.04.014;
RA Cornier A.S., Staehling-Hampton K., Delventhal K.M., Saga Y., Caubet J.-F.,
RA Sasaki N., Ellard S., Young E., Ramirez N., Carlo S.E., Torres J.,
RA Emans J.B., Turnpenny P.D., Pourquie O.;
RT "Mutations in the MESP2 gene cause spondylothoracic dysostosis/Jarcho-Levin
RT syndrome.";
RL Am. J. Hum. Genet. 82:1334-1341(2008).
RN [118]
RP CHARACTERIZATION OF VARIANT AD3 THR-213.
RX PubMed=18430735; DOI=10.1074/jbc.m801279200;
RA Shimojo M., Sahara N., Mizoroki T., Funamoto S., Morishima-Kawashima M.,
RA Kudo T., Takeda M., Ihara Y., Ichinose H., Takashima A.;
RT "Enzymatic characteristics of I213T mutant presenilin-1/gamma-secretase in
RT cell models and knock-in mouse brains: familial Alzheimer disease-linked
RT mutation impairs gamma-site cleavage of amyloid precursor protein C-
RT terminal fragment beta.";
RL J. Biol. Chem. 283:16488-16496(2008).
RN [119]
RP VARIANT AD3 VAL-381.
RX PubMed=19797784; DOI=10.1177/1533317509341464;
RA Dintchov Traykov L., Mehrabian S., Van den Broeck M.,
RA Radoslavova Raycheva M., Cruts M., Kirilova Jordanova A.,
RA Van Broeckhoven C.;
RT "Novel PSEN1 mutation in a Bulgarian patient with very early-onset
RT Alzheimer's disease, spastic paraparesis, and extrapyramidal signs.";
RL Am. J. Alzheimers Dis. Other Demen. 24:404-407(2009).
RN [120]
RP VARIANT AD3 ARG-217, AND CHARACTERIZATION OF VARIANT AD3 ARG-217.
RX PubMed=19667325; DOI=10.1212/wnl.0b013e3181b163ba;
RA Norton J.B., Cairns N.J., Chakraverty S., Wang J., Levitch D., Galvin J.E.,
RA Goate A.;
RT "Presenilin1 G217R mutation linked to Alzheimer disease with cotton wool
RT plaques.";
RL Neurology 73:480-482(2009).
RN [121]
RP VARIANT AD3 LEU-146.
RX PubMed=20164095; DOI=10.1212/wnl.0b013e3181d52785;
RA Bruni A.C., Bernardi L., Colao R., Rubino E., Smirne N., Frangipane F.,
RA Terni B., Curcio S.A., Mirabelli M., Clodomiro A., Di Lorenzo R.,
RA Maletta R., Anfossi M., Gallo M., Geracitano S., Tomaino C., Muraca M.G.,
RA Leotta A., Lio S.G., Pinessi L., Rainero I., Sorbi S., Nee L., Milan G.,
RA Pappata S., Postiglione A., Abbamondi N., Forloni G., St George Hyslop P.,
RA Rogaeva E., Bugiani O., Giaccone G., Foncin J.F., Spillantini M.G.,
RA Puccio G.;
RT "Worldwide distribution of PSEN1 Met146Leu mutation: a large variability
RT for a founder mutation.";
RL Neurology 74:798-806(2010).
RN [122]
RP VARIANT AD3 PHE-435, CHARACTERIZATION OF VARIANTS AD3 PHE-435; GLN-436 AND
RP SER-436, MUTAGENESIS OF PRO-433 AND LEU-435, AND FUNCTION.
RX PubMed=20460383; DOI=10.1074/jbc.m110.116962;
RA Heilig E.A., Xia W., Shen J., Kelleher R.J. III;
RT "A presenilin-1 mutation identified in familial Alzheimer disease with
RT cotton wool plaques causes a nearly complete loss of gamma-secretase
RT activity.";
RL J. Biol. Chem. 285:22350-22359(2010).
RN [123]
RP VARIANT AD3 ASP-206.
RX PubMed=21335660; DOI=10.3233/jad-2011-102031;
RA Wu Y.Y., Cheng I.H., Lee C.C., Chiu M.J., Lee M.J., Chen T.F., Hsu J.L.;
RT "Clinical phenotype of G206D mutation in the presenilin 1 gene in
RT pathologically confirmed familial Alzheimer's disease.";
RL J. Alzheimers Dis. 25:145-150(2011).
RN [124]
RP VARIANT CYS-315.
RX PubMed=21248752; DOI=10.1038/nature09639;
RA Varela I., Tarpey P., Raine K., Huang D., Ong C.K., Stephens P., Davies H.,
RA Jones D., Lin M.L., Teague J., Bignell G., Butler A., Cho J.,
RA Dalgliesh G.L., Galappaththige D., Greenman C., Hardy C., Jia M.,
RA Latimer C., Lau K.W., Marshall J., McLaren S., Menzies A., Mudie L.,
RA Stebbings L., Largaespada D.A., Wessels L.F.A., Richard S., Kahnoski R.J.,
RA Anema J., Tuveson D.A., Perez-Mancera P.A., Mustonen V., Fischer A.,
RA Adams D.J., Rust A., Chan-On W., Subimerb C., Dykema K., Furge K.,
RA Campbell P.J., Teh B.T., Stratton M.R., Futreal P.A.;
RT "Exome sequencing identifies frequent mutation of the SWI/SNF complex gene
RT PBRM1 in renal carcinoma.";
RL Nature 469:539-542(2011).
RN [125]
RP VARIANT AD3 ARG-235.
RX PubMed=21501661; DOI=10.1016/j.neulet.2011.03.084;
RA Antonell A., Balasa M., Oliva R., Llado A., Bosch B., Fabregat N.,
RA Fortea J., Molinuevo J.L., Sanchez-Valle R.;
RT "A novel PSEN1 gene mutation (L235R) associated with familial early-onset
RT Alzheimer's disease.";
RL Neurosci. Lett. 496:40-42(2011).
RN [126]
RP CHARACTERIZATION OF VARIANTS AD3 LEU-146; ARG-163 AND ALA-280.
RX PubMed=22461631; DOI=10.1074/jbc.m111.300483;
RA Chau D.M., Crump C.J., Villa J.C., Scheinberg D.A., Li Y.M.;
RT "Familial Alzheimer disease presenilin-1 mutations alter the active site
RT conformation of gamma-secretase.";
RL J. Biol. Chem. 287:17288-17296(2012).
RN [127]
RP VARIANTS AD3 ARG-134; ARG-163 AND VAL-262, AND VARIANT TYR-214.
RX PubMed=22503161; DOI=10.1016/j.neurobiolaging.2012.02.020;
RA Lohmann E., Guerreiro R.J., Erginel-Unaltuna N., Gurunlian N., Bilgic B.,
RA Gurvit H., Hanagasi H.A., Luu N., Emre M., Singleton A.;
RT "Identification of PSEN1 and PSEN2 gene mutations and variants in Turkish
RT dementia patients.";
RL Neurobiol. Aging 33:1850.E17-1850.E27(2012).
RN [128]
RP VARIANT AD3 PHE-159.
RX PubMed=23123781; DOI=10.1016/j.neulet.2012.10.037;
RA Kerchner G.A., Holbrook K.;
RT "Novel presenilin-1 Y159F sequence variant associated with early-onset
RT Alzheimer's disease.";
RL Neurosci. Lett. 531:142-144(2012).
RN [129]
RP CHARACTERIZATION OF VARIANTS AD3 PRO-166 AND GLN-436, AND MUTAGENESIS OF
RP ASP-257 AND ASP-385.
RX PubMed=22529981; DOI=10.1371/journal.pone.0035133;
RA Cacquevel M., Aeschbach L., Houacine J., Fraering P.C.;
RT "Alzheimer's disease-linked mutations in presenilin-1 result in a drastic
RT loss of activity in purified gamma-secretase complexes.";
RL PLoS ONE 7:E35133-E35133(2012).
RN [130]
RP CHARACTERIZATION OF VARIANTS AD3 PRO-166; ILE-278; ALA-384; VAL-392;
RP TYR-410 AND PHE-435.
RX PubMed=23843529; DOI=10.1523/jneurosci.0954-13.2013;
RA Heilig E.A., Gutti U., Tai T., Shen J., Kelleher R.J. III;
RT "Trans-dominant negative effects of pathogenic PSEN1 mutations on gamma-
RT secretase activity and Abeta production.";
RL J. Neurosci. 33:11606-11617(2013).
RN [131]
RP VARIANT AD3 PHE-381.
RX PubMed=24121961; DOI=10.3233/jad-131340;
RA Dolzhanskaya N., Gonzalez M.A., Sperziani F., Stefl S., Messing J.,
RA Wen G.Y., Alexov E., Zuchner S., Velinov M.;
RT "A novel p.Leu(381)Phe mutation in presenilin 1 is associated with very
RT early onset and unusually fast progressing dementia as well as lysosomal
RT inclusions typically seen in Kufs disease.";
RL J. Alzheimers Dis. 39:23-27(2014).
RN [132]
RP VARIANT AD3 VAL-153.
RX PubMed=24495933; DOI=10.1016/j.neulet.2014.01.016;
RA Cornejo-Olivas M.R., Yu C.E., Mazzetti P., Mata I.F., Meza M.,
RA Lindo-Samanamud S., Leverenz J.B., Bird T.D.;
RT "Clinical and molecular studies reveal a PSEN1 mutation (L153V) in a
RT Peruvian family with early-onset Alzheimer's disease.";
RL Neurosci. Lett. 563:140-143(2014).
RN [133]
RP VARIANT AD3 VAL-275.
RX PubMed=24582897; DOI=10.1016/j.neulet.2014.02.034;
RA Luedecke D., Becktepe J.S., Lehmbeck J.T., Finckh U., Yamamoto R., Jahn H.,
RA Boelmans K.;
RT "A novel presenilin 1 mutation (Ala275Val) as cause of early-onset familial
RT Alzheimer disease.";
RL Neurosci. Lett. 566:115-119(2014).
RN [134]
RP VARIANT AD3 THR-83.
RX PubMed=26145164; DOI=10.1016/j.neurobiolaging.2015.06.007;
RA Achouri-Rassas A., Ben Ali N., Fray S., Hadj Fredj S., Kechaou M.,
RA Zakraoui N.O., Cherif A., Chabbi S., Anane N., Messaoud T., Gouider R.,
RA Belal S.;
RT "Novel presenilin 1 mutation (p.I83T) in Tunisian family with early-onset
RT Alzheimer's disease.";
RL Neurobiol. Aging 36:2904.E09-2904.E11(2015).
RN [135]
RP VARIANTS AD3 ALA-206 AND VAL-378.
RX PubMed=27073747;
RA Ravenscroft T.A., Pottier C., Murray M.E., Baker M., Christopher E.,
RA Levitch D., Brown P.H., Barker W., Duara R., Greig-Custo M., Betancourt A.,
RA English M., Sun X., Ertekin-Taner N., Graff-Radford N.R., Dickson D.W.,
RA Rademakers R.;
RT "The presenilin 1 p.Gly206Ala mutation is a frequent cause of early-onset
RT Alzheimer's disease in Hispanics in Florida.";
RL Am. J. Neurodegener. Dis. 5:94-101(2016).
RN [136]
RP VARIANT AD3 THR-408.
RX PubMed=26549787; DOI=10.1016/j.neulet.2015.11.004;
RA Tedde A., Bartoli A., Piaceri I., Ferrara S., Bagnoli S., Serio A.,
RA Sorbi S., Nacmias B.;
RT "Novel presenilin 1 mutation (Ile408Thr) in an Italian family with late-
RT onset Alzheimer's disease.";
RL Neurosci. Lett. 610:150-153(2016).
RN [137]
RP VARIANT ARG-311, CHARACTERIZATION OF VARIANTS ALA-280 AND ARG-311, AND
RP FUNCTION.
RX PubMed=28269784; DOI=10.3233/jad-161188;
RA Dong J., Qin W., Wei C., Tang Y., Wang Q., Jia J.;
RT "A novel PSEN1 K311R mutation discovered in Chinese families with late-
RT onset Alzheimer's disease affects amyloid-beta production and tau
RT phosphorylation.";
RL J. Alzheimers Dis. 57:613-623(2017).
RN [138]
RP CHARACTERIZATION OF VARIANTS AD3 GLN-35; VAL-79; LEU-82; PRO-85; LEU-89;
RP SER-92; MET-94; PHE-96; LEU-97; HIS-115; ASN-116; ASP-120; LYS-120;
RP ARG-134; ASP-135; VAL-139; THR-143; LEU-146; ILE-147; VAL-153; ASN-154;
RP ARG-163; TYR-163; PRO-166; PRO-169; PHE-170; PRO-171; TRP-173; MET-174;
RP LEU-177; PRO-178; VAL-183; ASP-184; ALA-206; SER-206; ARG-209; VAL-209;
RP LEU-213; ARG-217; ARG-222; PHE-229; THR-231; LEU-233; THR-233; ARG-235;
RP PRO-235; VAL-235; ILE-237; GLU-246; SER-250; VAL-260; PHE-261; PHE-262;
RP ARG-263; LEU-264; SER-266; SER-267; GLY-269; VAL-271; ARG-274; VAL-275;
RP ALA-280; GLY-280; ARG-282; VAL-285; VAL-286; ILE-354; GLN-358; GLU-378;
RP VAL-378; VAL-381; ALA-384; ILE-390; VAL-392; VAL-394; THR-396; SER-405;
RP THR-409; TYR-410; PHE-418; PRO-426; GLU-431; PHE-435; SER-436 AND VAL-439,
RP CHARACTERIZATION OF VARIANT CMD1U GLY-333, AND MUTAGENESIS OF THR-99;
RP PHE-105; ARG-108; LEU-113; PRO-117; GLU-123; HIS-131; ALA-136; ILE-143;
RP LEU-150; TRP-165; ILE-168; PHE-176; GLU-184; ILE-202; SER-212; HIS-214;
RP LEU-219; GLN-223; LEU-226; SER-230; ILE-238; LYS-239; THR-245; LEU-248;
RP TYR-256; VAL-272; GLU-273; ARG-278; PRO-284; THR-291; ARG-352; SER-365;
RP ARG-377; PHE-386; VAL-391; VAL-412; LEU-420; LEU-424; ALA-434 AND ILE-437.
RX PubMed=27930341; DOI=10.1073/pnas.1618657114;
RA Sun L., Zhou R., Yang G., Shi Y.;
RT "Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro
RT production of Abeta42 and Abeta40 peptides by gamma-secretase.";
RL Proc. Natl. Acad. Sci. U.S.A. 114:E476-E485(2017).
RN [139]
RP VARIANT AD3 ILE-116.
RX PubMed=30200536; DOI=10.3390/ijms19092604;
RA Bagyinszky E., Lee H.M., Van Giau V., Koh S.B., Jeong J.H., An S.S.A.,
RA Kim S.;
RT "PSEN1 p.Thr116Ile variant in two Korean families with young onset
RT Alzheimer's disease.";
RL Int. J. Mol. Sci. 19:0-0(2018).
RN [140]
RP VARIANT AD3 ASN-116.
RX PubMed=29404783; DOI=10.1007/s00702-018-1850-z;
RA Sutovsky S., Smolek T., Turcani P., Petrovic R., Brandoburova P.,
RA Jadhav S., Novak P., Attems J., Zilka N.;
RT "Neuropathology and biochemistry of early onset familial Alzheimer's
RT disease caused by presenilin-1 missense mutation Thr116Asn.";
RL J. Neural Transm. 125:965-976(2018).
RN [141]
RP VARIANTS AD3 PHE-142 AND ASP-206.
RX PubMed=29175279; DOI=10.1016/j.neurobiolaging.2017.10.011;
RA Wang J.C., Alinaghi S., Tafakhori A., Sikora E., Azcona L.J.,
RA Karkheiran S., Goate A., Paisan-Ruiz C., Darvish H.;
RT "Genetic screening in two Iranian families with early-onset Alzheimer's
RT disease identified a novel PSEN1 mutation.";
RL Neurobiol. Aging 62:E15-E17(2018).
RN [142]
RP VARIANT AD3 ALA-417.
RX PubMed=30180983; DOI=10.1016/j.neurobiolaging.2018.08.003;
RA Giau V.V., Wang M.J., Bagyinszky E., Youn Y.C., An S.S.A., Kim S.;
RT "Novel PSEN1 p.Gly417Ala mutation in a Korean patient with early-onset
RT Alzheimer's disease with parkinsonism.";
RL Neurobiol. Aging 72:E13-E17(2018).
RN [143]
RP VARIANT AD3 PHE-170.
RX PubMed=29466804; DOI=10.1159/000485899;
RA Tiedt H.O., Benjamin B., Niedeggen M., Lueschow A.;
RT "Phenotypic variability in autosomal dominant familial Alzheimer disease
RT due to the S170F mutation of presenilin-1.";
RL Neurodegener. Dis. 18:57-68(2018).
CC -!- FUNCTION: Catalytic subunit of the gamma-secretase complex, an
CC endoprotease complex that catalyzes the intramembrane cleavage of
CC integral membrane proteins such as Notch receptors and APP (amyloid-
CC beta precursor protein) (PubMed:15274632, PubMed:10545183,
CC PubMed:10593990, PubMed:10206644, PubMed:10899933, PubMed:10811883,
CC PubMed:12679784, PubMed:12740439, PubMed:25043039, PubMed:26280335,
CC PubMed:30598546, PubMed:30630874, PubMed:28269784, PubMed:20460383).
CC Requires the presence of the other members of the gamma-secretase
CC complex for protease activity (PubMed:15274632, PubMed:25043039,
CC PubMed:26280335, PubMed:30598546, PubMed:30630874). Plays a role in
CC Notch and Wnt signaling cascades and regulation of downstream processes
CC via its role in processing key regulatory proteins, and by regulating
CC cytosolic CTNNB1 levels (PubMed:9738936, PubMed:10593990,
CC PubMed:10899933, PubMed:10811883). Stimulates cell-cell adhesion via
CC its interaction with CDH1; this stabilizes the complexes between CDH1
CC (E-cadherin) and its interaction partners CTNNB1 (beta-catenin), CTNND1
CC and JUP (gamma-catenin) (PubMed:11953314). Under conditions of
CC apoptosis or calcium influx, cleaves CDH1 (PubMed:11953314). This
CC promotes the disassembly of the complexes between CDH1 and CTNND1, JUP
CC and CTNNB1, increases the pool of cytoplasmic CTNNB1, and thereby
CC negatively regulates Wnt signaling (PubMed:9738936, PubMed:11953314).
CC Required for normal embryonic brain and skeleton development, and for
CC normal angiogenesis (By similarity). Mediates the proteolytic cleavage
CC of EphB2/CTF1 into EphB2/CTF2 (PubMed:17428795, PubMed:28269784). The
CC holoprotein functions as a calcium-leak channel that allows the passive
CC movement of calcium from endoplasmic reticulum to cytosol and is
CC therefore involved in calcium homeostasis (PubMed:25394380,
CC PubMed:16959576). Involved in the regulation of neurite outgrowth
CC (PubMed:15004326, PubMed:20460383). Is a regulator of presynaptic
CC facilitation, spike transmission and synaptic vesicles replenishment in
CC a process that depends on gamma-secretase activity. It acts through the
CC control of SYT7 presynaptic expression (By similarity).
CC {ECO:0000250|UniProtKB:P49769, ECO:0000269|PubMed:10206644,
CC ECO:0000269|PubMed:10545183, ECO:0000269|PubMed:10593990,
CC ECO:0000269|PubMed:10811883, ECO:0000269|PubMed:10899933,
CC ECO:0000269|PubMed:11953314, ECO:0000269|PubMed:12679784,
CC ECO:0000269|PubMed:12740439, ECO:0000269|PubMed:15004326,
CC ECO:0000269|PubMed:15274632, ECO:0000269|PubMed:15341515,
CC ECO:0000269|PubMed:16305624, ECO:0000269|PubMed:16959576,
CC ECO:0000269|PubMed:17428795, ECO:0000269|PubMed:20460383,
CC ECO:0000269|PubMed:25043039, ECO:0000269|PubMed:25394380,
CC ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:28269784,
CC ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874,
CC ECO:0000269|PubMed:9738936}.
CC -!- SUBUNIT: Homodimer. The functional gamma-secretase complex is composed
CC of at least four polypeptides: a presenilin homodimer (PSEN1 or PSEN2),
CC nicastrin (NCSTN), APH1 (APH1A/APH1B) and PEN2 (PubMed:15274632,
CC PubMed:12679784, PubMed:12740439, PubMed:25043039, PubMed:26280335,
CC PubMed:25394380, PubMed:30598546, PubMed:30630874). Such minimal
CC complex is sufficient for secretase activity (PubMed:15274632,
CC PubMed:12679784, PubMed:12740439, PubMed:25043039, PubMed:26280335,
CC PubMed:30598546, PubMed:30630874). Other components which are
CC associated with the complex include SLC25A64, SLC5A7, PHB and PSEN1
CC isoform 3. As part of the gamma-secretase complex, interacts with CRB2
CC (via transmembrane domain) (PubMed:20299451). Predominantly heterodimer
CC of a N-terminal (NTF) and a C-terminal (CTF) endoproteolytical fragment
CC (PubMed:15274632). Associates with proteolytic processed C-terminal
CC fragments C83 and C99 of the amyloid precursor protein (APP) (via
CC transmembrane domain) (PubMed:30630874). Associates with NOTCH1 (via
CC transmembrane domain) (PubMed:10593990, PubMed:30598546). Associates
CC with cadherin/catenin adhesion complexes through direct binding to CDH1
CC or CDH2 (PubMed:11953314, PubMed:14515347, PubMed:16126725).
CC Interaction with CDH1 stabilizes the complex and stimulates cell-cell
CC aggregation (PubMed:11953314). Interaction with CDH2 is essential for
CC trafficking of CDH2 from the endoplasmic reticulum to the plasma
CC membrane (PubMed:14515347). Interacts with CTNND2, CTNNB1, CTNND1, JUP,
CC HERPUD1, FLNA, FLNB, MTCH1, PKP4 and PARL (PubMed:9738936,
CC PubMed:9437013, PubMed:10551805, PubMed:10037471, PubMed:11953314,
CC PubMed:11799129, PubMed:16126725). Interacts through its N-terminus
CC with GFAP (isoform 2) (PubMed:12058025). Interacts with DOCK3 (By
CC similarity). Interacts with isoform 1 and isoform 3 of UBQLN1
CC (PubMed:21143716). {ECO:0000250|UniProtKB:P49769,
CC ECO:0000269|PubMed:10037471, ECO:0000269|PubMed:10551805,
CC ECO:0000269|PubMed:11799129, ECO:0000269|PubMed:11953314,
CC ECO:0000269|PubMed:12058025, ECO:0000269|PubMed:12679784,
CC ECO:0000269|PubMed:12740439, ECO:0000269|PubMed:14515347,
CC ECO:0000269|PubMed:15274632, ECO:0000269|PubMed:16126725,
CC ECO:0000269|PubMed:20299451, ECO:0000269|PubMed:21143716,
CC ECO:0000269|PubMed:25043039, ECO:0000269|PubMed:25394380,
CC ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:30598546,
CC ECO:0000269|PubMed:30630874, ECO:0000269|PubMed:9437013,
CC ECO:0000269|PubMed:9738936}.
CC -!- INTERACTION:
CC P49768; Q02410: APBA1; NbExp=4; IntAct=EBI-297277, EBI-368690;
CC P49768; P05067: APP; NbExp=6; IntAct=EBI-297277, EBI-77613;
CC P49768; P05067-4: APP; NbExp=4; IntAct=EBI-297277, EBI-302641;
CC P49768; P56817: BACE1; NbExp=6; IntAct=EBI-297277, EBI-2433139;
CC P49768; Q16543: CDC37; NbExp=3; IntAct=EBI-297277, EBI-295634;
CC P49768; Q9BQ95: ECSIT; NbExp=4; IntAct=EBI-297277, EBI-712452;
CC P49768; Q92542: NCSTN; NbExp=6; IntAct=EBI-297277, EBI-998440;
CC P49768; Q9NZ42: PSENEN; NbExp=4; IntAct=EBI-297277, EBI-998468;
CC P49768; P50502: ST13; NbExp=3; IntAct=EBI-297277, EBI-357285;
CC P49768; P55061: TMBIM6; NbExp=12; IntAct=EBI-297277, EBI-1045825;
CC P49768; P49755: TMED10; NbExp=4; IntAct=EBI-297277, EBI-998422;
CC P49768; Q9NZC2: TREM2; NbExp=5; IntAct=EBI-297277, EBI-14036387;
CC P49768; P98084: Apba2; Xeno; NbExp=2; IntAct=EBI-297277, EBI-81669;
CC P49768-2; P63010-2: AP2B1; NbExp=6; IntAct=EBI-11047108, EBI-11529439;
CC P49768-2; P05067: APP; NbExp=6; IntAct=EBI-11047108, EBI-77613;
CC P49768-2; P16870: CPE; NbExp=3; IntAct=EBI-11047108, EBI-711320;
CC P49768-2; Q5D0E6-2: DALRD3; NbExp=3; IntAct=EBI-11047108, EBI-9090939;
CC P49768-2; Q9H816: DCLRE1B; NbExp=3; IntAct=EBI-11047108, EBI-3508943;
CC P49768-2; Q9UHY8: FEZ2; NbExp=3; IntAct=EBI-11047108, EBI-396453;
CC P49768-2; Q06787-7: FMR1; NbExp=3; IntAct=EBI-11047108, EBI-25856644;
CC P49768-2; P02792: FTL; NbExp=3; IntAct=EBI-11047108, EBI-713279;
CC P49768-2; P68431: H3C12; NbExp=6; IntAct=EBI-11047108, EBI-79722;
CC P49768-2; Q12891: HYAL2; NbExp=3; IntAct=EBI-11047108, EBI-2806068;
CC P49768-2; Q6DN90-2: IQSEC1; NbExp=6; IntAct=EBI-11047108, EBI-21911304;
CC P49768-2; Q9NVX7-2: KBTBD4; NbExp=3; IntAct=EBI-11047108, EBI-25871195;
CC P49768-2; Q9BYQ4: KRTAP9-2; NbExp=3; IntAct=EBI-11047108, EBI-1044640;
CC P49768-2; Q9BYZ2: LDHAL6B; NbExp=6; IntAct=EBI-11047108, EBI-1108377;
CC P49768-2; Q8TDB4: MGARP; NbExp=6; IntAct=EBI-11047108, EBI-4397720;
CC P49768-2; A4FUJ8: MKL1; NbExp=6; IntAct=EBI-11047108, EBI-21250407;
CC P49768-2; Q9Y605: MRFAP1; NbExp=3; IntAct=EBI-11047108, EBI-995714;
CC P49768-2; Q86WS3: OOSP2; NbExp=3; IntAct=EBI-11047108, EBI-25888682;
CC P49768-2; Q96FW1: OTUB1; NbExp=3; IntAct=EBI-11047108, EBI-1058491;
CC P49768-2; Q13113: PDZK1IP1; NbExp=6; IntAct=EBI-11047108, EBI-716063;
CC P49768-2; P53350: PLK1; NbExp=3; IntAct=EBI-11047108, EBI-476768;
CC P49768-2; O14494: PLPP1; NbExp=3; IntAct=EBI-11047108, EBI-2865290;
CC P49768-2; Q9NZ42: PSENEN; NbExp=3; IntAct=EBI-11047108, EBI-998468;
CC P49768-2; Q6ZNA4-2: RNF111; NbExp=6; IntAct=EBI-11047108, EBI-21535400;
CC P49768-2; Q9ULX5: RNF112; NbExp=6; IntAct=EBI-11047108, EBI-25829984;
CC P49768-2; Q8N488: RYBP; NbExp=6; IntAct=EBI-11047108, EBI-752324;
CC P49768-2; Q2NKQ1-4: SGSM1; NbExp=3; IntAct=EBI-11047108, EBI-10182463;
CC P49768-2; Q3KNW5: SLC10A6; NbExp=3; IntAct=EBI-11047108, EBI-18159983;
CC P49768-2; Q99932-2: SPAG8; NbExp=6; IntAct=EBI-11047108, EBI-11959123;
CC P49768-2; O00300: TNFRSF11B; NbExp=3; IntAct=EBI-11047108, EBI-15481185;
CC P49768-2; Q9GZS3: WDR61; NbExp=6; IntAct=EBI-11047108, EBI-358545;
CC P49768-2; Q96NC0: ZMAT2; NbExp=6; IntAct=EBI-11047108, EBI-2682299;
CC PRO_0000025591; Q63053: Arc; Xeno; NbExp=3; IntAct=EBI-2606326, EBI-5275794;
CC PRO_0000025592; P35613: BSG; NbExp=6; IntAct=EBI-2606356, EBI-750709;
CC PRO_0000025592; Q92542: NCSTN; NbExp=2; IntAct=EBI-2606356, EBI-998440;
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum
CC {ECO:0000269|PubMed:25394380}. Endoplasmic reticulum membrane
CC {ECO:0000269|PubMed:10593990, ECO:0000269|PubMed:8574969,
CC ECO:0000269|PubMed:9738936, ECO:0000305|PubMed:10037471,
CC ECO:0000305|PubMed:15274632}; Multi-pass membrane protein
CC {ECO:0000269|PubMed:25043039, ECO:0000269|PubMed:25918421,
CC ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:26623517,
CC ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874}. Golgi
CC apparatus membrane {ECO:0000269|PubMed:10593990,
CC ECO:0000269|PubMed:8574969, ECO:0000305|PubMed:10037471,
CC ECO:0000305|PubMed:15274632}; Multi-pass membrane protein
CC {ECO:0000269|PubMed:25043039, ECO:0000269|PubMed:25918421,
CC ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:26623517,
CC ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874}. Cytoplasmic
CC granule {ECO:0000269|PubMed:11987239}. Cell membrane
CC {ECO:0000269|PubMed:10593990, ECO:0000269|PubMed:11953314,
CC ECO:0000269|PubMed:11987239, ECO:0000269|PubMed:21143716}; Multi-pass
CC membrane protein {ECO:0000269|PubMed:25918421,
CC ECO:0000269|PubMed:26623517, ECO:0000269|PubMed:30598546,
CC ECO:0000269|PubMed:30630874}. Cell projection, growth cone
CC {ECO:0000269|PubMed:15004326}. Early endosome
CC {ECO:0000269|PubMed:25394380}. Early endosome membrane
CC {ECO:0000305|PubMed:25394380}; Multi-pass membrane protein
CC {ECO:0000269|PubMed:25918421, ECO:0000269|PubMed:26623517,
CC ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874}. Cell
CC projection, neuron projection {ECO:0000269|PubMed:15004326}. Cell
CC projection, axon {ECO:0000250|UniProtKB:Q4JIM4}. Synapse
CC {ECO:0000250|UniProtKB:Q4JIM4}. Note=Translocates with bound NOTCH1
CC from the endoplasmic reticulum and/or Golgi to the cell surface
CC (PubMed:10593990). Colocalizes with CDH1/2 at sites of cell-cell
CC contact. Colocalizes with CTNNB1 in the endoplasmic reticulum and the
CC proximity of the plasma membrane (PubMed:9738936). Also present in
CC azurophil granules of neutrophils (PubMed:11987239). Colocalizes with
CC UBQLN1 in the cell membrane and in cytoplasmic juxtanuclear structures
CC called aggresomes (PubMed:21143716). {ECO:0000269|PubMed:10593990,
CC ECO:0000269|PubMed:11987239, ECO:0000269|PubMed:21143716,
CC ECO:0000269|PubMed:9738936}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=7;
CC Name=1; Synonyms=I-467;
CC IsoId=P49768-1; Sequence=Displayed;
CC Name=2; Synonyms=I-463;
CC IsoId=P49768-2; Sequence=VSP_005191;
CC Name=3; Synonyms=I-374;
CC IsoId=P49768-3; Sequence=VSP_005191, VSP_005192;
CC Name=4; Synonyms=Minilin;
CC IsoId=P49768-4; Sequence=VSP_007986, VSP_007987;
CC Name=5;
CC IsoId=P49768-5; Sequence=VSP_005192;
CC Name=6;
CC IsoId=P49768-6; Sequence=VSP_012288;
CC Name=7;
CC IsoId=P49768-7; Sequence=VSP_041440;
CC -!- TISSUE SPECIFICITY: Detected in azurophile granules in neutrophils and
CC in platelet cytoplasmic granules (at protein level) (PubMed:11987239).
CC Expressed in a wide range of tissues including various regions of the
CC brain, liver, spleen and lymph nodes (PubMed:7596406, PubMed:8641442,
CC PubMed:8574969). {ECO:0000269|PubMed:11987239,
CC ECO:0000269|PubMed:7596406, ECO:0000269|PubMed:8574969,
CC ECO:0000269|PubMed:8641442}.
CC -!- DOMAIN: The PAL motif is required for normal active site conformation.
CC {ECO:0000269|PubMed:16305624}.
CC -!- DOMAIN: Substrates, such as NOTCH1 and APP peptides, are bound between
CC PSEN1 transmembrane domains and via the first lumenal loop and the
CC cytoplasmic loop between the sixth and seventh transmembrane domains.
CC Substrate binding causes a conformation change and formation of an
CC intermolecular antiparallel beta-sheet between PSEN1 and its
CC substrates. {ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874}.
CC -!- PTM: Heterogeneous proteolytic processing generates N-terminal (NTF)
CC and C-terminal (CTF) fragments of approximately 35 and 20 kDa,
CC respectively. During apoptosis, the C-terminal fragment (CTF) is
CC further cleaved by caspase-3 to produce the fragment, PS1-CTF12.
CC {ECO:0000269|PubMed:10545183, ECO:0000269|PubMed:15274632,
CC ECO:0000269|PubMed:9173929, ECO:0000269|PubMed:9485372}.
CC -!- PTM: After endoproteolysis, the C-terminal fragment (CTF) is
CC phosphorylated on serine residues by PKA and/or PKC. Phosphorylation on
CC Ser-346 inhibits endoproteolysis. {ECO:0000269|PubMed:14576165,
CC ECO:0000269|PubMed:9144240}.
CC -!- DISEASE: Alzheimer disease 3 (AD3) [MIM:607822]: A familial early-onset
CC form of Alzheimer disease. Alzheimer disease is a neurodegenerative
CC disorder characterized by progressive dementia, loss of cognitive
CC abilities, and deposition of fibrillar amyloid proteins as
CC intraneuronal neurofibrillary tangles, extracellular amyloid plaques
CC and vascular amyloid deposits. The major constituents of these plaques
CC are neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42,
CC that are produced by the proteolysis of the transmembrane APP protein.
CC The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved
CC products, such as C31, are also implicated in neuronal death.
CC {ECO:0000269|PubMed:10025789, ECO:0000269|PubMed:10090481,
CC ECO:0000269|PubMed:10200054, ECO:0000269|PubMed:10208579,
CC ECO:0000269|PubMed:10439444, ECO:0000269|PubMed:10441572,
CC ECO:0000269|PubMed:10447269, ECO:0000269|PubMed:10533070,
CC ECO:0000269|PubMed:10631141, ECO:0000269|PubMed:10644793,
CC ECO:0000269|PubMed:11027672, ECO:0000269|PubMed:11524469,
CC ECO:0000269|PubMed:11561050, ECO:0000269|PubMed:11568920,
CC ECO:0000269|PubMed:11701593, ECO:0000269|PubMed:11710891,
CC ECO:0000269|PubMed:11796781, ECO:0000269|PubMed:11920851,
CC ECO:0000269|PubMed:12048239, ECO:0000269|PubMed:12058025,
CC ECO:0000269|PubMed:12370477, ECO:0000269|PubMed:12484344,
CC ECO:0000269|PubMed:12493737, ECO:0000269|PubMed:12552037,
CC ECO:0000269|PubMed:15004326, ECO:0000269|PubMed:15122701,
CC ECO:0000269|PubMed:15364419, ECO:0000269|PubMed:15534188,
CC ECO:0000269|PubMed:15534260, ECO:0000269|PubMed:15851849,
CC ECO:0000269|PubMed:16305624, ECO:0000269|PubMed:16344340,
CC ECO:0000269|PubMed:16628450, ECO:0000269|PubMed:16752394,
CC ECO:0000269|PubMed:16897084, ECO:0000269|PubMed:16959576,
CC ECO:0000269|PubMed:17366635, ECO:0000269|PubMed:17428795,
CC ECO:0000269|PubMed:17502474, ECO:0000269|PubMed:18430735,
CC ECO:0000269|PubMed:19667325, ECO:0000269|PubMed:19797784,
CC ECO:0000269|PubMed:20164095, ECO:0000269|PubMed:20460383,
CC ECO:0000269|PubMed:21335660, ECO:0000269|PubMed:21501661,
CC ECO:0000269|PubMed:22461631, ECO:0000269|PubMed:22503161,
CC ECO:0000269|PubMed:22529981, ECO:0000269|PubMed:23123781,
CC ECO:0000269|PubMed:23843529, ECO:0000269|PubMed:24121961,
CC ECO:0000269|PubMed:24495933, ECO:0000269|PubMed:24582897,
CC ECO:0000269|PubMed:25394380, ECO:0000269|PubMed:26145164,
CC ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:26549787,
CC ECO:0000269|PubMed:27073747, ECO:0000269|PubMed:27930341,
CC ECO:0000269|PubMed:29175279, ECO:0000269|PubMed:29404783,
CC ECO:0000269|PubMed:29466804, ECO:0000269|PubMed:30180983,
CC ECO:0000269|PubMed:30200536, ECO:0000269|PubMed:7550356,
CC ECO:0000269|PubMed:7596406, ECO:0000269|PubMed:7651536,
CC ECO:0000269|PubMed:8634711, ECO:0000269|PubMed:8634712,
CC ECO:0000269|PubMed:8733303, ECO:0000269|PubMed:8837617,
CC ECO:0000269|PubMed:9172170, ECO:0000269|PubMed:9225696,
CC ECO:0000269|PubMed:9298817, ECO:0000269|PubMed:9384602,
CC ECO:0000269|PubMed:9507958, ECO:0000269|PubMed:9521423,
CC ECO:0000269|PubMed:9719376, ECO:0000269|PubMed:9831473,
CC ECO:0000269|PubMed:9833068, ECO:0000269|Ref.93}. Note=The disease is
CC caused by variants affecting the gene represented in this entry.
CC -!- DISEASE: Frontotemporal dementia (FTD) [MIM:600274]: A form of dementia
CC characterized by pathologic finding of frontotemporal lobar
CC degeneration, presenile dementia with behavioral changes, deterioration
CC of cognitive capacities and loss of memory. In some cases, parkinsonian
CC symptoms are prominent. Neuropathological changes include
CC frontotemporal atrophy often associated with atrophy of the basal
CC ganglia, substantia nigra, amygdala. In most cases, protein tau
CC deposits are found in glial cells and/or neurons.
CC {ECO:0000269|PubMed:11094121}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Cardiomyopathy, dilated 1U (CMD1U) [MIM:613694]: A disorder
CC characterized by ventricular dilation and impaired systolic function,
CC resulting in congestive heart failure and arrhythmia. Patients are at
CC risk of premature death. {ECO:0000269|PubMed:17186461,
CC ECO:0000269|PubMed:27930341}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Acne inversa, familial, 3 (ACNINV3) [MIM:613737]: A chronic
CC relapsing inflammatory disease of the hair follicles characterized by
CC recurrent draining sinuses, painful skin abscesses, and disfiguring
CC scars. Manifestations typically appear after puberty.
CC {ECO:0000269|PubMed:20929727}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Pick disease of the brain (PIDB) [MIM:172700]: A rare form of
CC dementia pathologically defined by severe atrophy, neuronal loss and
CC gliosis. It is characterized by the occurrence of tau-positive
CC inclusions, swollen neurons (Pick cells) and argentophilic neuronal
CC inclusions known as Pick bodies that disproportionally affect the
CC frontal and temporal cortical regions. Clinical features include
CC aphasia, apraxia, confusion, anomia, memory loss and personality
CC deterioration. {ECO:0000269|PubMed:15122701}. Note=The gene represented
CC in this entry may be involved in disease pathogenesis.
CC -!- MISCELLANEOUS: [Isoform 3]: May be produced at very low levels due to a
CC premature stop codon in the mRNA, leading to nonsense-mediated mRNA
CC decay. {ECO:0000305}.
CC -!- MISCELLANEOUS: [Isoform 5]: May be produced at very low levels due to a
CC premature stop codon in the mRNA, leading to nonsense-mediated mRNA
CC decay. {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the peptidase A22A family. {ECO:0000305}.
CC -!- WEB RESOURCE: Name=Alzheimer Research Forum; Note=Presenilins
CC mutations;
CC URL="https://www.alzforum.org/mutations/search?genes%255B%255D=348";
CC ---------------------------------------------------------------------------
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DR EMBL; L42110; AAB46416.1; -; mRNA.
DR EMBL; L76517; AAB46370.1; -; mRNA.
DR EMBL; L76528; AAB46371.1; -; Genomic_DNA.
DR EMBL; L76519; AAB46371.1; JOINED; Genomic_DNA.
DR EMBL; L76520; AAB46371.1; JOINED; Genomic_DNA.
DR EMBL; L76521; AAB46371.1; JOINED; Genomic_DNA.
DR EMBL; L76522; AAB46371.1; JOINED; Genomic_DNA.
DR EMBL; L76523; AAB46371.1; JOINED; Genomic_DNA.
DR EMBL; L76524; AAB46371.1; JOINED; Genomic_DNA.
DR EMBL; L76525; AAB46371.1; JOINED; Genomic_DNA.
DR EMBL; L76526; AAB46371.1; JOINED; Genomic_DNA.
DR EMBL; L76527; AAB46371.1; JOINED; Genomic_DNA.
DR EMBL; U40379; AAB05894.1; -; mRNA.
DR EMBL; U40380; AAB05895.1; -; mRNA.
DR EMBL; AJ008005; CAA07825.1; -; mRNA.
DR EMBL; AF109907; AAC97960.1; -; Genomic_DNA.
DR EMBL; AF416717; AAL16811.1; -; mRNA.
DR EMBL; AK312531; BAG35430.1; -; mRNA.
DR EMBL; AC004858; AAF19253.1; -; Genomic_DNA.
DR EMBL; AC004858; AAF19254.1; -; Genomic_DNA.
DR EMBL; CH471061; EAW81092.1; -; Genomic_DNA.
DR EMBL; BC011729; AAH11729.1; -; mRNA.
DR EMBL; D84149; BAA20883.1; -; Genomic_DNA.
DR CCDS; CCDS9812.1; -. [P49768-1]
DR CCDS; CCDS9813.1; -. [P49768-2]
DR PIR; S58396; S58396.
DR PIR; S63683; S63683.
DR PIR; S63684; S63684.
DR RefSeq; NP_000012.1; NM_000021.3. [P49768-1]
DR RefSeq; NP_015557.2; NM_007318.2. [P49768-2]
DR RefSeq; XP_005267921.1; XM_005267864.2. [P49768-1]
DR RefSeq; XP_005267923.1; XM_005267866.1. [P49768-2]
DR RefSeq; XP_011535273.1; XM_011536971.2.
DR RefSeq; XP_011535274.1; XM_011536972.2. [P49768-1]
DR RefSeq; XP_011535275.1; XM_011536973.1. [P49768-2]
DR RefSeq; XP_011535276.1; XM_011536974.1. [P49768-2]
DR PDB; 2KR6; NMR; -; A=292-467.
DR PDB; 4UIS; EM; 4.40 A; B=81-463.
DR PDB; 5A63; EM; 3.40 A; B=1-467.
DR PDB; 5FN2; EM; 4.20 A; B=1-467.
DR PDB; 5FN3; EM; 4.10 A; B=1-467.
DR PDB; 5FN4; EM; 4.00 A; B=1-467.
DR PDB; 5FN5; EM; 4.30 A; B=1-467.
DR PDB; 6IDF; EM; 2.70 A; B=1-467.
DR PDB; 6IYC; EM; 2.60 A; B=1-467.
DR PDB; 6LQG; EM; 3.10 A; B=1-467.
DR PDB; 6LR4; EM; 3.00 A; B=1-467.
DR PDB; 7C9I; EM; 3.10 A; B=1-467.
DR PDB; 7D8X; EM; 2.60 A; B=1-467.
DR PDBsum; 2KR6; -.
DR PDBsum; 4UIS; -.
DR PDBsum; 5A63; -.
DR PDBsum; 5FN2; -.
DR PDBsum; 5FN3; -.
DR PDBsum; 5FN4; -.
DR PDBsum; 5FN5; -.
DR PDBsum; 6IDF; -.
DR PDBsum; 6IYC; -.
DR PDBsum; 6LQG; -.
DR PDBsum; 6LR4; -.
DR PDBsum; 7C9I; -.
DR PDBsum; 7D8X; -.
DR AlphaFoldDB; P49768; -.
DR SMR; P49768; -.
DR BioGRID; 111642; 196.
DR ComplexPortal; CPX-2176; Gamma-secretase complex, APH1A-PSEN1 variant.
DR ComplexPortal; CPX-4233; Gamma-secretase complex, APH1B-PSEN1 variant.
DR CORUM; P49768; -.
DR DIP; DIP-1134N; -.
DR ELM; P49768; -.
DR IntAct; P49768; 257.
DR MINT; P49768; -.
DR STRING; 9606.ENSP00000326366; -.
DR BindingDB; P49768; -.
DR ChEMBL; CHEMBL2473; -.
DR GuidetoPHARMACOLOGY; 2402; -.
DR MEROPS; A22.001; -.
DR TCDB; 1.A.54.1.1; the presenilin er ca(2+) leak channel (presenilin) family.
DR iPTMnet; P49768; -.
DR PhosphoSitePlus; P49768; -.
DR SwissPalm; P49768; -.
DR BioMuta; PSEN1; -.
DR DMDM; 1709856; -.
DR EPD; P49768; -.
DR jPOST; P49768; -.
DR MassIVE; P49768; -.
DR MaxQB; P49768; -.
DR PaxDb; P49768; -.
DR PeptideAtlas; P49768; -.
DR PRIDE; P49768; -.
DR ProteomicsDB; 56106; -. [P49768-1]
DR ProteomicsDB; 56107; -. [P49768-2]
DR ProteomicsDB; 56108; -. [P49768-3]
DR ProteomicsDB; 56109; -. [P49768-4]
DR ProteomicsDB; 56110; -. [P49768-5]
DR ProteomicsDB; 56111; -. [P49768-6]
DR ProteomicsDB; 56112; -. [P49768-7]
DR Antibodypedia; 3480; 1003 antibodies from 44 providers.
DR DNASU; 5663; -.
DR Ensembl; ENST00000324501.10; ENSP00000326366.5; ENSG00000080815.19. [P49768-1]
DR Ensembl; ENST00000357710.8; ENSP00000350342.4; ENSG00000080815.19. [P49768-2]
DR Ensembl; ENST00000394157.7; ENSP00000377712.3; ENSG00000080815.19. [P49768-4]
DR Ensembl; ENST00000394164.5; ENSP00000377719.1; ENSG00000080815.19. [P49768-2]
DR Ensembl; ENST00000553855.5; ENSP00000452242.1; ENSG00000080815.19. [P49768-5]
DR Ensembl; ENST00000555386.5; ENSP00000450845.1; ENSG00000080815.19. [P49768-3]
DR Ensembl; ENST00000557511.5; ENSP00000451429.1; ENSG00000080815.19. [P49768-6]
DR GeneID; 5663; -.
DR KEGG; hsa:5663; -.
DR MANE-Select; ENST00000324501.10; ENSP00000326366.5; NM_000021.4; NP_000012.1.
DR UCSC; uc001xnq.5; human. [P49768-1]
DR CTD; 5663; -.
DR DisGeNET; 5663; -.
DR GeneCards; PSEN1; -.
DR GeneReviews; PSEN1; -.
DR HGNC; HGNC:9508; PSEN1.
DR HPA; ENSG00000080815; Low tissue specificity.
DR MalaCards; PSEN1; -.
DR MIM; 104311; gene.
DR MIM; 172700; phenotype.
DR MIM; 600274; phenotype.
DR MIM; 607822; phenotype.
DR MIM; 613694; phenotype.
DR MIM; 613737; phenotype.
DR neXtProt; NX_P49768; -.
DR NIAGADS; ENSG00000080815; -.
DR OpenTargets; ENSG00000080815; -.
DR Orphanet; 275864; Behavioral variant of frontotemporal dementia.
DR Orphanet; 1020; Early-onset autosomal dominant Alzheimer disease.
DR Orphanet; 154; Familial isolated dilated cardiomyopathy.
DR Orphanet; 387; NON RARE IN EUROPE: Hidradenitis suppurativa.
DR Orphanet; 100070; Progressive non-fluent aphasia.
DR Orphanet; 100069; Semantic dementia.
DR PharmGKB; PA33855; -.
DR VEuPathDB; HostDB:ENSG00000080815; -.
DR eggNOG; KOG2736; Eukaryota.
DR GeneTree; ENSGT00940000158751; -.
DR HOGENOM; CLU_022975_3_0_1; -.
DR InParanoid; P49768; -.
DR OMA; MQPVADP; -.
DR PhylomeDB; P49768; -.
DR TreeFam; TF315040; -.
DR PathwayCommons; P49768; -.
DR Reactome; R-HSA-1251985; Nuclear signaling by ERBB4.
DR Reactome; R-HSA-1474228; Degradation of the extracellular matrix.
DR Reactome; R-HSA-193692; Regulated proteolysis of p75NTR.
DR Reactome; R-HSA-205043; NRIF signals cell death from the nucleus.
DR Reactome; R-HSA-2122948; Activated NOTCH1 Transmits Signal to the Nucleus.
DR Reactome; R-HSA-2644606; Constitutive Signaling by NOTCH1 PEST Domain Mutants.
DR Reactome; R-HSA-2894862; Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants.
DR Reactome; R-HSA-2979096; NOTCH2 Activation and Transmission of Signal to the Nucleus.
DR Reactome; R-HSA-3928665; EPH-ephrin mediated repulsion of cells.
DR Reactome; R-HSA-6798695; Neutrophil degranulation.
DR Reactome; R-HSA-9013507; NOTCH3 Activation and Transmission of Signal to the Nucleus.
DR Reactome; R-HSA-9013700; NOTCH4 Activation and Transmission of Signal to the Nucleus.
DR Reactome; R-HSA-9017802; Noncanonical activation of NOTCH3.
DR SignaLink; P49768; -.
DR SIGNOR; P49768; -.
DR BioGRID-ORCS; 5663; 16 hits in 1082 CRISPR screens.
DR ChiTaRS; PSEN1; human.
DR EvolutionaryTrace; P49768; -.
DR GeneWiki; PSEN1; -.
DR GenomeRNAi; 5663; -.
DR Pharos; P49768; Tchem.
DR PRO; PR:P49768; -.
DR Proteomes; UP000005640; Chromosome 14.
DR RNAct; P49768; protein.
DR Bgee; ENSG00000080815; Expressed in middle frontal gyrus and 200 other tissues.
DR ExpressionAtlas; P49768; baseline and differential.
DR Genevisible; P49768; HS.
DR GO; GO:0016235; C:aggresome; IDA:UniProtKB.
DR GO; GO:0070161; C:anchoring junction; IEA:UniProtKB-KW.
DR GO; GO:0016324; C:apical plasma membrane; IBA:GO_Central.
DR GO; GO:0035577; C:azurophil granule membrane; TAS:Reactome.
DR GO; GO:0005938; C:cell cortex; IBA:GO_Central.
DR GO; GO:0030054; C:cell junction; IDA:HPA.
DR GO; GO:0009986; C:cell surface; IBA:GO_Central.
DR GO; GO:0005813; C:centrosome; IDA:UniProtKB.
DR GO; GO:0035253; C:ciliary rootlet; IBA:GO_Central.
DR GO; GO:0043198; C:dendritic shaft; IBA:GO_Central.
DR GO; GO:0031901; C:early endosome membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:HGNC-UCL.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IC:ComplexPortal.
DR GO; GO:0070765; C:gamma-secretase complex; IDA:UniProtKB.
DR GO; GO:0005794; C:Golgi apparatus; IDA:UniProtKB.
DR GO; GO:0000139; C:Golgi membrane; IC:ComplexPortal.
DR GO; GO:0030426; C:growth cone; IDA:UniProtKB.
DR GO; GO:0016021; C:integral component of membrane; IDA:UniProtKB.
DR GO; GO:0005887; C:integral component of plasma membrane; IDA:HGNC-UCL.
DR GO; GO:0099056; C:integral component of presynaptic membrane; IEA:Ensembl.
DR GO; GO:0000776; C:kinetochore; IDA:UniProtKB.
DR GO; GO:0005765; C:lysosomal membrane; IBA:GO_Central.
DR GO; GO:0016020; C:membrane; IDA:MGI.
DR GO; GO:0045121; C:membrane raft; IDA:UniProtKB.
DR GO; GO:0005743; C:mitochondrial inner membrane; IBA:GO_Central.
DR GO; GO:0005739; C:mitochondrion; IDA:UniProtKB.
DR GO; GO:0031594; C:neuromuscular junction; IBA:GO_Central.
DR GO; GO:0043005; C:neuron projection; IDA:UniProtKB.
DR GO; GO:0043025; C:neuronal cell body; IBA:GO_Central.
DR GO; GO:0031965; C:nuclear membrane; IDA:UniProtKB.
DR GO; GO:0005640; C:nuclear outer membrane; IDA:MGI.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0005634; C:nucleus; IMP:CAFA.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; IDA:ComplexPortal.
DR GO; GO:0032991; C:protein-containing complex; IMP:CAFA.
DR GO; GO:0005791; C:rough endoplasmic reticulum; IDA:UniProtKB.
DR GO; GO:0042383; C:sarcolemma; IEA:Ensembl.
DR GO; GO:0005790; C:smooth endoplasmic reticulum; IDA:UniProtKB.
DR GO; GO:0008021; C:synaptic vesicle; IEA:Ensembl.
DR GO; GO:0030018; C:Z disc; IBA:GO_Central.
DR GO; GO:0042500; F:aspartic endopeptidase activity, intramembrane cleaving; IDA:UniProtKB.
DR GO; GO:0004190; F:aspartic-type endopeptidase activity; NAS:ARUK-UCL.
DR GO; GO:0051117; F:ATPase binding; IPI:ARUK-UCL.
DR GO; GO:0008013; F:beta-catenin binding; IPI:UniProtKB.
DR GO; GO:0045296; F:cadherin binding; IBA:GO_Central.
DR GO; GO:0005262; F:calcium channel activity; IMP:UniProtKB.
DR GO; GO:0004175; F:endopeptidase activity; IDA:MGI.
DR GO; GO:0070851; F:growth factor receptor binding; IPI:ARUK-UCL.
DR GO; GO:0030165; F:PDZ domain binding; IPI:UniProtKB.
DR GO; GO:0042987; P:amyloid precursor protein catabolic process; IDA:ARUK-UCL.
DR GO; GO:0042982; P:amyloid precursor protein metabolic process; IDA:UniProtKB.
DR GO; GO:0034205; P:amyloid-beta formation; IDA:ARUK-UCL.
DR GO; GO:0050435; P:amyloid-beta metabolic process; IBA:GO_Central.
DR GO; GO:0097190; P:apoptotic signaling pathway; IEA:Ensembl.
DR GO; GO:0048143; P:astrocyte activation; IGI:ARUK-UCL.
DR GO; GO:0002265; P:astrocyte activation involved in immune response; IGI:ARUK-UCL.
DR GO; GO:0000045; P:autophagosome assembly; IEA:Ensembl.
DR GO; GO:0001568; P:blood vessel development; IEA:Ensembl.
DR GO; GO:0048854; P:brain morphogenesis; IEA:Ensembl.
DR GO; GO:0021870; P:Cajal-Retzius cell differentiation; IEA:Ensembl.
DR GO; GO:0006816; P:calcium ion transport; IBA:GO_Central.
DR GO; GO:0001708; P:cell fate specification; IEA:Ensembl.
DR GO; GO:0098609; P:cell-cell adhesion; IMP:MGI.
DR GO; GO:1904646; P:cellular response to amyloid-beta; IGI:ARUK-UCL.
DR GO; GO:0006974; P:cellular response to DNA damage stimulus; IDA:ARUK-UCL.
DR GO; GO:0021549; P:cerebellum development; IEA:Ensembl.
DR GO; GO:0021795; P:cerebral cortex cell migration; IEA:Ensembl.
DR GO; GO:0015871; P:choline transport; IEA:Ensembl.
DR GO; GO:0021904; P:dorsal/ventral neural tube patterning; IEA:Ensembl.
DR GO; GO:0030326; P:embryonic limb morphogenesis; IEA:Ensembl.
DR GO; GO:0032469; P:endoplasmic reticulum calcium ion homeostasis; IDA:MGI.
DR GO; GO:0050673; P:epithelial cell proliferation; IEA:Ensembl.
DR GO; GO:0001947; P:heart looping; IEA:Ensembl.
DR GO; GO:0002244; P:hematopoietic progenitor cell differentiation; IEA:Ensembl.
DR GO; GO:0035556; P:intracellular signal transduction; IEA:InterPro.
DR GO; GO:0098712; P:L-glutamate import across plasma membrane; IEA:Ensembl.
DR GO; GO:0007611; P:learning or memory; IGI:ARUK-UCL.
DR GO; GO:0040011; P:locomotion; IEA:Ensembl.
DR GO; GO:0006509; P:membrane protein ectodomain proteolysis; IDA:HGNC-UCL.
DR GO; GO:0031293; P:membrane protein intracellular domain proteolysis; IDA:ComplexPortal.
DR GO; GO:0007613; P:memory; IGI:ARUK-UCL.
DR GO; GO:0006839; P:mitochondrial transport; IEA:Ensembl.
DR GO; GO:0043011; P:myeloid dendritic cell differentiation; IEA:Ensembl.
DR GO; GO:0043066; P:negative regulation of apoptotic process; IDA:UniProtKB.
DR GO; GO:2001234; P:negative regulation of apoptotic signaling pathway; IEA:Ensembl.
DR GO; GO:0050771; P:negative regulation of axonogenesis; IEA:Ensembl.
DR GO; GO:1904797; P:negative regulation of core promoter binding; IMP:CAFA.
DR GO; GO:0007175; P:negative regulation of epidermal growth factor-activated receptor activity; IEA:Ensembl.
DR GO; GO:0010629; P:negative regulation of gene expression; IGI:ARUK-UCL.
DR GO; GO:0043524; P:negative regulation of neuron apoptotic process; IEA:Ensembl.
DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; IMP:CAFA.
DR GO; GO:2000059; P:negative regulation of ubiquitin-dependent protein catabolic process; IEA:Ensembl.
DR GO; GO:0051444; P:negative regulation of ubiquitin-protein transferase activity; IEA:Ensembl.
DR GO; GO:0003407; P:neural retina development; IEA:Ensembl.
DR GO; GO:0051402; P:neuron apoptotic process; IEA:Ensembl.
DR GO; GO:0070050; P:neuron cellular homeostasis; IEA:Ensembl.
DR GO; GO:0048666; P:neuron development; IEA:Ensembl.
DR GO; GO:0001764; P:neuron migration; IEA:Ensembl.
DR GO; GO:1990535; P:neuron projection maintenance; IGI:ARUK-UCL.
DR GO; GO:0007220; P:Notch receptor processing; IDA:ARUK-UCL.
DR GO; GO:0007219; P:Notch signaling pathway; IEA:UniProtKB-KW.
DR GO; GO:1905908; P:positive regulation of amyloid fibril formation; IGI:ARUK-UCL.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IEA:Ensembl.
DR GO; GO:0043085; P:positive regulation of catalytic activity; IDA:HGNC-UCL.
DR GO; GO:0050820; P:positive regulation of coagulation; IEA:Ensembl.
DR GO; GO:0060999; P:positive regulation of dendritic spine development; IMP:CACAO.
DR GO; GO:0010628; P:positive regulation of gene expression; IGI:ARUK-UCL.
DR GO; GO:0045821; P:positive regulation of glycolytic process; IGI:ARUK-UCL.
DR GO; GO:0002038; P:positive regulation of L-glutamate import across plasma membrane; IEA:Ensembl.
DR GO; GO:0043406; P:positive regulation of MAP kinase activity; IEA:Ensembl.
DR GO; GO:0042327; P:positive regulation of phosphorylation; IGI:ARUK-UCL.
DR GO; GO:0032436; P:positive regulation of proteasomal ubiquitin-dependent protein catabolic process; IEA:Ensembl.
DR GO; GO:0032092; P:positive regulation of protein binding; IGI:ARUK-UCL.
DR GO; GO:0042307; P:positive regulation of protein import into nucleus; IMP:UniProtKB.
DR GO; GO:0001921; P:positive regulation of receptor recycling; IEA:Ensembl.
DR GO; GO:0045893; P:positive regulation of transcription, DNA-templated; IMP:CACAO.
DR GO; GO:0032760; P:positive regulation of tumor necrosis factor production; IGI:ARUK-UCL.
DR GO; GO:0009791; P:post-embryonic development; IEA:Ensembl.
DR GO; GO:0006486; P:protein glycosylation; IEA:Ensembl.
DR GO; GO:0016485; P:protein processing; IDA:HGNC-UCL.
DR GO; GO:0015031; P:protein transport; IEA:Ensembl.
DR GO; GO:0060828; P:regulation of canonical Wnt signaling pathway; ISS:UniProtKB.
DR GO; GO:0010468; P:regulation of gene expression; IGI:ARUK-UCL.
DR GO; GO:0010975; P:regulation of neuron projection development; IMP:UniProtKB.
DR GO; GO:0042325; P:regulation of phosphorylation; IDA:UniProtKB.
DR GO; GO:0060075; P:regulation of resting membrane potential; IEA:Ensembl.
DR GO; GO:0048167; P:regulation of synaptic plasticity; IEA:Ensembl.
DR GO; GO:0051966; P:regulation of synaptic transmission, glutamatergic; IEA:Ensembl.
DR GO; GO:0006979; P:response to oxidative stress; IEA:Ensembl.
DR GO; GO:0051208; P:sequestering of calcium ion; IEA:Ensembl.
DR GO; GO:0048705; P:skeletal system morphogenesis; IEA:Ensembl.
DR GO; GO:0043589; P:skin morphogenesis; IEA:Ensembl.
DR GO; GO:0051563; P:smooth endoplasmic reticulum calcium ion homeostasis; IBA:GO_Central.
DR GO; GO:0001756; P:somitogenesis; IEA:Ensembl.
DR GO; GO:0050808; P:synapse organization; IGI:ARUK-UCL.
DR GO; GO:0016080; P:synaptic vesicle targeting; IEA:Ensembl.
DR GO; GO:0002286; P:T cell activation involved in immune response; IEA:Ensembl.
DR GO; GO:0050852; P:T cell receptor signaling pathway; IEA:Ensembl.
DR GO; GO:0048538; P:thymus development; IEA:Ensembl.
DR DisProt; DP01292; -.
DR Gene3D; 1.10.472.100; -; 1.
DR InterPro; IPR002031; Pept_A22A_PS1.
DR InterPro; IPR001108; Peptidase_A22A.
DR InterPro; IPR006639; Preselin/SPP.
DR InterPro; IPR042524; Presenilin_C.
DR PANTHER; PTHR10202; PTHR10202; 1.
DR Pfam; PF01080; Presenilin; 1.
DR PRINTS; PR01072; PRESENILIN.
DR PRINTS; PR01073; PRESENILIN1.
DR SMART; SM00730; PSN; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Alzheimer disease; Amyloidosis;
KW Apoptosis; Cardiomyopathy; Cell adhesion; Cell membrane; Cell projection;
KW Direct protein sequencing; Disease variant; Endoplasmic reticulum;
KW Endosome; Golgi apparatus; Hydrolase; Membrane; Neurodegeneration;
KW Notch signaling pathway; Phosphoprotein; Protease; Reference proteome;
KW Synapse; Transmembrane; Transmembrane helix.
FT CHAIN 1..298
FT /note="Presenilin-1 NTF subunit"
FT /id="PRO_0000025591"
FT CHAIN 299..467
FT /note="Presenilin-1 CTF subunit"
FT /id="PRO_0000025592"
FT CHAIN 346..467
FT /note="Presenilin-1 CTF12"
FT /id="PRO_0000236055"
FT TOPO_DOM 1..82
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:26280335"
FT TRANSMEM 83..103
FT /note="Helical"
FT /evidence="ECO:0000269|PubMed:26280335"
FT TOPO_DOM 104..132
FT /note="Lumenal"
FT /evidence="ECO:0000269|PubMed:26280335"
FT TRANSMEM 133..153
FT /note="Helical"
FT /evidence="ECO:0000269|PubMed:26280335"
FT TOPO_DOM 154..166
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:26280335"
FT TRANSMEM 167..189
FT /note="Helical"
FT /evidence="ECO:0000269|PubMed:26280335"
FT TOPO_DOM 190..194
FT /note="Lumenal"
FT /evidence="ECO:0000269|PubMed:26280335"
FT TRANSMEM 195..216
FT /note="Helical"
FT /evidence="ECO:0000269|PubMed:26280335"
FT TOPO_DOM 217..220
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:26280335"
FT TRANSMEM 221..241
FT /note="Helical"
FT /evidence="ECO:0000269|PubMed:26280335"
FT TOPO_DOM 242..248
FT /note="Lumenal"
FT /evidence="ECO:0000269|PubMed:26280335"
FT TRANSMEM 249..272
FT /note="Helical"
FT /evidence="ECO:0000269|PubMed:26280335"
FT TOPO_DOM 273..380
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:26280335"
FT TRANSMEM 381..401
FT /note="Helical"
FT /evidence="ECO:0000269|PubMed:26280335"
FT TOPO_DOM 402..407
FT /note="Lumenal"
FT /evidence="ECO:0000269|PubMed:26280335"
FT TRANSMEM 408..428
FT /note="Helical"
FT /evidence="ECO:0000269|PubMed:26280335"
FT TOPO_DOM 429..432
FT /note="Cytoplasmic"
FT /evidence="ECO:0000269|PubMed:26280335"
FT TRANSMEM 433..453
FT /note="Helical"
FT /evidence="ECO:0000269|PubMed:26280335"
FT TOPO_DOM 454..467
FT /note="Lumenal"
FT /evidence="ECO:0000269|PubMed:26280335"
FT REGION 13..68
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 288..290
FT /note="Important for cleavage of target proteins"
FT /evidence="ECO:0000269|PubMed:30598546"
FT REGION 305..333
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 322..450
FT /note="Required for interaction with CTNNB1"
FT /evidence="ECO:0000269|PubMed:9738936"
FT REGION 372..399
FT /note="Required for interaction with CTNND2"
FT /evidence="ECO:0000269|PubMed:10037471"
FT REGION 377..381
FT /note="Important for cleavage of target proteins"
FT /evidence="ECO:0000269|PubMed:30598546"
FT REGION 432..434
FT /note="Important for cleavage of target proteins"
FT /evidence="ECO:0000269|PubMed:30598546"
FT REGION 464..467
FT /note="Interaction with MTCH1"
FT /evidence="ECO:0000269|PubMed:10551805"
FT MOTIF 433..435
FT /note="PAL"
FT /evidence="ECO:0000305|PubMed:16305624"
FT COMPBIAS 13..27
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 28..47
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 305..329
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 257
FT /evidence="ECO:0000305|PubMed:10206644,
FT ECO:0000305|PubMed:10899933, ECO:0000305|PubMed:15341515"
FT ACT_SITE 385
FT /evidence="ECO:0000305|PubMed:10206644,
FT ECO:0000305|PubMed:10899933, ECO:0000305|PubMed:15341515,
FT ECO:0000305|PubMed:30598546, ECO:0000305|PubMed:30630874"
FT SITE 291..292
FT /note="Cleavage; alternate"
FT /evidence="ECO:0000269|PubMed:9173929"
FT SITE 292..293
FT /note="Cleavage; alternate"
FT /evidence="ECO:0000269|PubMed:9173929"
FT SITE 298..299
FT /note="Cleavage"
FT /evidence="ECO:0000269|PubMed:9173929"
FT SITE 345..346
FT /note="Cleavage; by caspase"
FT /evidence="ECO:0000269|PubMed:9485372"
FT MOD_RES 43
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:17081983,
FT ECO:0007744|PubMed:21406692, ECO:0007744|PubMed:23186163"
FT MOD_RES 51
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:P97887"
FT MOD_RES 310
FT /note="Phosphoserine; by PKA"
FT /evidence="ECO:0000269|PubMed:14576165"
FT MOD_RES 346
FT /note="Phosphoserine; by PKC"
FT /evidence="ECO:0000269|PubMed:14576165"
FT MOD_RES 367
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:21406692,
FT ECO:0007744|PubMed:23186163"
FT VAR_SEQ 26..29
FT /note="Missing (in isoform 2 and isoform 3)"
FT /evidence="ECO:0000303|PubMed:15489334,
FT ECO:0000303|PubMed:7596406, ECO:0000303|PubMed:8641442"
FT /id="VSP_005191"
FT VAR_SEQ 162..184
FT /note="IHAWLIISSLLLLFFFSFIYLGE -> SMRHRSLLSTLFFLWLGILVTVT
FT (in isoform 4)"
FT /evidence="ECO:0000303|Ref.3"
FT /id="VSP_007986"
FT VAR_SEQ 185..467
FT /note="Missing (in isoform 4)"
FT /evidence="ECO:0000303|Ref.3"
FT /id="VSP_007987"
FT VAR_SEQ 257..289
FT /note="Missing (in isoform 7)"
FT /evidence="ECO:0000305"
FT /id="VSP_041440"
FT VAR_SEQ 319..467
FT /note="STERESQDTVAENDDGGFSEEWEAQRDSHLGPHRSTPESRAAVQELSSSILA
FT GEDPEERGVKLGLGDFIFYSVLVGKASATASGDWNTTIACFVAILIGLCLTLLLLAIFK
FT KALPALPISITFGLVFYFATDYLVQPFMDQLAFHQFYI -> RACLPPAAINLLSIAPM
FT APRLFMPKGACRPTAQKGSHKTLLQRMMMAGSVRNGKPRGTVI (in isoform 3
FT and isoform 5)"
FT /evidence="ECO:0000303|PubMed:8641442, ECO:0000303|Ref.5"
FT /id="VSP_005192"
FT VAR_SEQ 319..376
FT /note="Missing (in isoform 6)"
FT /evidence="ECO:0000305"
FT /id="VSP_012288"
FT VARIANT 35
FT /note="R -> Q (in AD3; unknown pathological significance;
FT decreased protease activity with APP; dbSNP:rs63750592)"
FT /evidence="ECO:0000269|PubMed:11524469,
FT ECO:0000269|PubMed:27930341"
FT /id="VAR_075260"
FT VARIANT 79
FT /note="A -> V (in AD3; also found in late-onset Alzheimer
FT disease; impaired protease activity with APP; results in
FT altered amyloid-beta production and increased amyloid-beta
FT 42/amyloid-beta 40 ratio; no effect on interaction with
FT GFAP; dbSNP:rs63749824)"
FT /evidence="ECO:0000269|PubMed:10631141,
FT ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:12058025,
FT ECO:0000269|PubMed:16752394, ECO:0000269|PubMed:17366635,
FT ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:9384602"
FT /id="VAR_006413"
FT VARIANT 82
FT /note="V -> L (in AD3; decreased protease activity with
FT APP; no effect on interaction with GFAP; dbSNP:rs63749967)"
FT /evidence="ECO:0000269|PubMed:10441572,
FT ECO:0000269|PubMed:12058025, ECO:0000269|PubMed:27930341,
FT ECO:0000269|PubMed:8634712"
FT /id="VAR_006414"
FT VARIANT 83
FT /note="I -> T (in AD3)"
FT /evidence="ECO:0000269|PubMed:26145164"
FT /id="VAR_075261"
FT VARIANT 85
FT /note="L -> P (in AD3; the patient also manifest spastic
FT paraparesis and apraxia; loss of protease activity with APP
FT in vitro; altered amyloid-beta production in cells
FT transfected with the mutant and increased amyloid-beta 42/
FT amyloid-beta 40 ratio; dbSNP:rs63750599)"
FT /evidence="ECO:0000269|PubMed:15534188,
FT ECO:0000269|PubMed:27930341"
FT /id="VAR_081228"
FT VARIANT 89
FT /note="V -> L (in AD3; decreased protease activity with
FT APP; increased amyloid-beta 42/amyloid-beta 40 ratio;
FT dbSNP:rs63750815)"
FT /evidence="ECO:0000269|PubMed:11796781"
FT /id="VAR_081229"
FT VARIANT 92
FT /note="C -> S (in AD3; loss of protease activity with APP;
FT dbSNP:rs63751141)"
FT /evidence="ECO:0000269|PubMed:11027672,
FT ECO:0000269|PubMed:27930341"
FT /id="VAR_016214"
FT VARIANT 94
FT /note="V -> M (in AD3; unknown pathological significance;
FT reduced protease activity with APP; no relevant change in
FT amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63750831)"
FT /evidence="ECO:0000269|PubMed:11568920"
FT /id="VAR_081230"
FT VARIANT 96
FT /note="V -> F (in AD3; loss of protease activity with APP;
FT dbSNP:rs63750601)"
FT /evidence="ECO:0000269|PubMed:27930341,
FT ECO:0000269|PubMed:8733303"
FT /id="VAR_006415"
FT VARIANT 97
FT /note="V -> L (in AD3; unknown pathological significance;
FT slightly reduced protease activity with APP;
FT dbSNP:rs63750852)"
FT /evidence="ECO:0000269|PubMed:15851849,
FT ECO:0000269|PubMed:27930341"
FT /id="VAR_081231"
FT VARIANT 105
FT /note="F -> L (in AD3; dbSNP:rs63750321)"
FT /evidence="ECO:0000269|PubMed:10631141"
FT /id="VAR_009208"
FT VARIANT 113
FT /note="L -> P (in frontotemporal dementia;
FT dbSNP:rs63751399)"
FT /evidence="ECO:0000269|PubMed:11094121"
FT /id="VAR_016215"
FT VARIANT 115
FT /note="Y -> C (in AD3; dbSNP:rs63750450)"
FT /evidence="ECO:0000269|PubMed:11524469,
FT ECO:0000269|PubMed:12552037, ECO:0000269|PubMed:9384602"
FT /id="VAR_006416"
FT VARIANT 115
FT /note="Y -> H (in AD3; impaired protease activity with APP
FT and increased amyloid-beta 42/amyloid-beta 40 ratio)"
FT /evidence="ECO:0000269|PubMed:10441572,
FT ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:8634712"
FT /id="VAR_006417"
FT VARIANT 116
FT /note="T -> I (in AD3; dbSNP:rs63750730)"
FT /evidence="ECO:0000269|PubMed:30200536"
FT /id="VAR_081232"
FT VARIANT 116
FT /note="T -> N (in AD3; unusual amyloid cotton wool plaques
FT detected in one patient's brain; severe decrease of
FT protease activity with APP; results in increased amyloid-
FT beta 42/amyloid-beta 40 ratio; dbSNP:rs63750730)"
FT /evidence="ECO:0000269|PubMed:10439444,
FT ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:27930341,
FT ECO:0000269|PubMed:29404783"
FT /id="VAR_010120"
FT VARIANT 117
FT /note="P -> L (in AD3; impaired ability to cleave Ephb2/
FT CTF1; results in altered amyloid-beta production and
FT increased amyloid-beta 42/amyloid-beta 40 ratio; impaired
FT regulation of neurite outgrowth; dbSNP:rs63749805)"
FT /evidence="ECO:0000269|PubMed:15004326,
FT ECO:0000269|PubMed:17428795, ECO:0000269|PubMed:9507958"
FT /id="VAR_009209"
FT VARIANT 117
FT /note="P -> S (in AD3; results in altered amyloid-beta
FT production and increased amyloid-beta 42/amyloid-beta 40
FT ratio; impaired regulation of neurite outgrowth;
FT dbSNP:rs63750550)"
FT /evidence="ECO:0000269|PubMed:15004326"
FT /id="VAR_081233"
FT VARIANT 120
FT /note="E -> D (in AD3; impaired protease activity with APP
FT and increased amyloid-beta 42/amyloid-beta 40 ratio;
FT dbSNP:rs63751272)"
FT /evidence="ECO:0000269|PubMed:10441572,
FT ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:9521423"
FT /id="VAR_006418"
FT VARIANT 120
FT /note="E -> K (in AD3; impaired protease activity with APP
FT and increased amyloid-beta 42/amyloid-beta 40 ratio;
FT dbSNP:rs63750800)"
FT /evidence="ECO:0000269|PubMed:27930341"
FT /id="VAR_006419"
FT VARIANT 134
FT /note="L -> R (in AD3; uncertain pathological significance;
FT loss of protease activity with APP; dbSNP:rs1595002439)"
FT /evidence="ECO:0000269|PubMed:22503161,
FT ECO:0000269|PubMed:27930341"
FT /id="VAR_070023"
FT VARIANT 135
FT /note="N -> D (in AD3; impaired protease activity with APP
FT and increased amyloid-beta 42/amyloid-beta 40 ratio;
FT dbSNP:rs63750353)"
FT /evidence="ECO:0000269|PubMed:27930341,
FT ECO:0000269|PubMed:9225696"
FT /id="VAR_010121"
FT VARIANT 139
FT /note="M -> I (in AD3; dbSNP:rs63750522)"
FT /id="VAR_006420"
FT VARIANT 139
FT /note="M -> K (in AD3; dbSNP:rs63751106)"
FT /evidence="ECO:0000269|PubMed:9719376"
FT /id="VAR_010122"
FT VARIANT 139
FT /note="M -> T (in AD3; dbSNP:rs63751106)"
FT /evidence="ECO:0000269|PubMed:10441572,
FT ECO:0000269|PubMed:8634712"
FT /id="VAR_006421"
FT VARIANT 139
FT /note="M -> V (in AD3; increased amyloid-beta 42/amyloid-
FT beta 40 ratio; dbSNP:rs63751037)"
FT /evidence="ECO:0000269|PubMed:10631141,
FT ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:7550356"
FT /id="VAR_006422"
FT VARIANT 142
FT /note="V -> F (in AD3; unknown pathological significance)"
FT /evidence="ECO:0000269|PubMed:29175279"
FT /id="VAR_081234"
FT VARIANT 143
FT /note="I -> F (in AD3; dbSNP:rs63750322)"
FT /evidence="ECO:0000269|PubMed:10090481"
FT /id="VAR_006423"
FT VARIANT 143
FT /note="I -> T (in AD3; impaired protease activity with APP;
FT results in altered amyloid-beta production and increased
FT amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63750004)"
FT /evidence="ECO:0000269|PubMed:11524469,
FT ECO:0000269|PubMed:11568920, ECO:0000269|PubMed:15122701,
FT ECO:0000269|PubMed:16752394, ECO:0000269|PubMed:27930341,
FT ECO:0000269|PubMed:8634711"
FT /id="VAR_006424"
FT VARIANT 146
FT /note="M -> I (in AD3; dbSNP:rs63750391)"
FT /evidence="ECO:0000269|PubMed:11524469,
FT ECO:0000269|PubMed:12552037"
FT /id="VAR_006425"
FT VARIANT 146
FT /note="M -> L (in AD3; disease phenotype shows high
FT clinical variability; founder mutation originating from
FT Southern Italy and distributed worldwide; alters the
FT conformation of the active site; slightly increased
FT protease activity with APP; decreased activity for Notch1
FT cleavage; no loss of its ability to cleave Ephb2/CTF1;
FT dbSNP:rs63750306)"
FT /evidence="ECO:0000269|PubMed:10441572,
FT ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:17428795,
FT ECO:0000269|PubMed:20164095, ECO:0000269|PubMed:22461631,
FT ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:7596406"
FT /id="VAR_006426"
FT VARIANT 146
FT /note="M -> V (in AD3; loss of function as calcium-leak
FT channel; results in calcium overload in the endoplasmic
FT reticulum; dbSNP:rs63750306)"
FT /evidence="ECO:0000269|PubMed:11524469,
FT ECO:0000269|PubMed:16959576, ECO:0000269|PubMed:7550356"
FT /id="VAR_006427"
FT VARIANT 147
FT /note="T -> I (in AD3; results in altered amyloid-beta
FT production and increased amyloid-beta 42/amyloid-beta 40
FT ratio; dbSNP:rs63750907)"
FT /evidence="ECO:0000269|PubMed:10441572,
FT ECO:0000269|PubMed:27930341"
FT /id="VAR_010123"
FT VARIANT 153
FT /note="L -> V (in AD3; abolishes protease activity with APP
FT resulting in decreased amyloid-beta 42 and amyloid-beta 40
FT production; dbSNP:rs63751441)"
FT /evidence="ECO:0000269|PubMed:12552037,
FT ECO:0000269|PubMed:24495933, ECO:0000269|PubMed:27930341"
FT /id="VAR_081235"
FT VARIANT 154
FT /note="Y -> C (in AD3; unknown pathological significance;
FT dbSNP:rs63751292)"
FT /evidence="ECO:0000269|PubMed:12552037"
FT /id="VAR_081236"
FT VARIANT 154
FT /note="Y -> N (in AD3; disease phenotype includes spastic
FT paraparesis; abolishes protease activity with APP resulting
FT in decreased amyloid-beta 42 and amyloid-beta 40
FT production; dbSNP:rs63750588)"
FT /evidence="ECO:0000269|PubMed:15364419,
FT ECO:0000269|PubMed:27930341"
FT /id="VAR_081237"
FT VARIANT 156
FT /note="Y -> FTY (in AD3; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:11524469"
FT /id="VAR_075262"
FT VARIANT 159
FT /note="Y -> F (in AD3; unknown pathological significance;
FT dbSNP:rs778630379)"
FT /evidence="ECO:0000269|PubMed:23123781"
FT /id="VAR_081238"
FT VARIANT 163
FT /note="H -> R (in AD3; abolishes protease activity with
FT APP; decreased activity for Notch cleavage;
FT dbSNP:rs63750590)"
FT /evidence="ECO:0000269|PubMed:10441572,
FT ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:22461631,
FT ECO:0000269|PubMed:22503161, ECO:0000269|PubMed:27930341,
FT ECO:0000269|PubMed:7596406, ECO:0000269|PubMed:8634712,
FT ECO:0000269|PubMed:8733303, ECO:0000269|PubMed:9521423"
FT /id="VAR_006428"
FT VARIANT 163
FT /note="H -> Y (in AD3; slightly increased protease activity
FT with APP and slightly increased amyloid-beta 42 production;
FT dbSNP:rs63749885)"
FT /evidence="ECO:0000269|PubMed:27930341,
FT ECO:0000269|PubMed:7550356"
FT /id="VAR_006429"
FT VARIANT 165
FT /note="W -> C (in AD3; dbSNP:rs63751484)"
FT /evidence="ECO:0000269|PubMed:10441572"
FT /id="VAR_010124"
FT VARIANT 166
FT /note="L -> P (in AD3; onset in adolescence; severe
FT decrease of protease activity with APP; results in altered
FT amyloid-beta production and increased amyloid-beta 42/
FT amyloid-beta 40 ratio; results in reduced Notch
FT proteolysis; dbSNP:rs63750265)"
FT /evidence="ECO:0000269|PubMed:12048239,
FT ECO:0000269|PubMed:22529981, ECO:0000269|PubMed:23843529,
FT ECO:0000269|PubMed:27930341"
FT /id="VAR_016216"
FT VARIANT 168
FT /note="Missing (in AD3; unknown pathological significance;
FT abolishes protease activity with APP resulting in decreased
FT amyloid-beta 42 and amyloid-beta 40 production)"
FT /evidence="ECO:0000269|PubMed:12552037"
FT /id="VAR_081239"
FT VARIANT 169
FT /note="S -> L (in AD3; dbSNP:rs63751210)"
FT /evidence="ECO:0000269|PubMed:9831473"
FT /id="VAR_006430"
FT VARIANT 169
FT /note="S -> P (in AD3; results in altered amyloid-beta
FT production and increased amyloid-beta 42/amyloid-beta 40
FT ratio; dbSNP:rs63750418)"
FT /evidence="ECO:0000269|PubMed:10025789,
FT ECO:0000269|PubMed:27930341"
FT /id="VAR_006431"
FT VARIANT 170
FT /note="S -> F (in AD3; results in altered amyloid-beta
FT production and increased amyloid-beta 42/amyloid-beta 40
FT ratio; dbSNP:rs63750577)"
FT /evidence="ECO:0000269|PubMed:16344340,
FT ECO:0000269|PubMed:17502474, ECO:0000269|PubMed:27930341,
FT ECO:0000269|PubMed:29466804"
FT /id="VAR_081240"
FT VARIANT 171
FT /note="L -> P (in AD3; abolishes protease activity with
FT APP; dbSNP:rs63750963)"
FT /evidence="ECO:0000269|PubMed:12552037,
FT ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:9833068"
FT /id="VAR_006432"
FT VARIANT 173
FT /note="L -> W (in AD3; results in altered amyloid-beta
FT production and increased amyloid-beta 42/amyloid-beta 40
FT ratio; dbSNP:rs63750299)"
FT /evidence="ECO:0000269|PubMed:10441572,
FT ECO:0000269|PubMed:27930341"
FT /id="VAR_010125"
FT VARIANT 174
FT /note="L -> M (in AD3; results in altered amyloid-beta
FT production and increased amyloid-beta 42/amyloid-beta 40
FT ratio; dbSNP:rs63751144)"
FT /evidence="ECO:0000269|PubMed:12484344,
FT ECO:0000269|PubMed:27930341"
FT /id="VAR_016217"
FT VARIANT 177
FT /note="F -> L (in AD3; results in altered amyloid-beta
FT production and increased amyloid-beta 42/amyloid-beta 40
FT ratio; dbSNP:rs63749911)"
FT /evidence="ECO:0000269|PubMed:11524469,
FT ECO:0000269|PubMed:27930341"
FT /id="VAR_075263"
FT VARIANT 177
FT /note="F -> S (in AD3; unknown pathological significance;
FT dbSNP:rs63749806)"
FT /evidence="ECO:0000269|PubMed:11524469"
FT /id="VAR_075264"
FT VARIANT 178
FT /note="S -> P (in AD3; unknown pathological significance;
FT abolishes protease activity with APP; dbSNP:rs63750155)"
FT /evidence="ECO:0000269|PubMed:11524469,
FT ECO:0000269|PubMed:27930341"
FT /id="VAR_075265"
FT VARIANT 183
FT /note="G -> V (in PIDB and AD3; neuropathologic examination
FT of brain sections from the patient shows the presence of
FT Pick bodies and absence of beta-amyloid plaques; unknown
FT pathological significance; results in altered amyloid-beta
FT production and increased amyloid-beta 42/amyloid-beta 40
FT ratio in vitro; dbSNP:rs63751068)"
FT /evidence="ECO:0000269|PubMed:15122701,
FT ECO:0000269|PubMed:27930341"
FT /id="VAR_081241"
FT VARIANT 184
FT /note="E -> D (in AD3; results in altered amyloid-beta
FT production and increased amyloid-beta 42/amyloid-beta 40
FT ratio; dbSNP:rs63750311)"
FT /evidence="ECO:0000269|PubMed:12552037,
FT ECO:0000269|PubMed:27930341"
FT /id="VAR_081242"
FT VARIANT 205
FT /note="F -> L (in dbSNP:rs1042864)"
FT /id="VAR_011876"
FT VARIANT 206
FT /note="G -> A (in AD3; results in altered amyloid-beta
FT production and increased amyloid-beta 42/amyloid-beta 40
FT ratio; dbSNP:rs63750082)"
FT /evidence="ECO:0000269|PubMed:11524469,
FT ECO:0000269|PubMed:11710891, ECO:0000269|PubMed:27073747,
FT ECO:0000269|PubMed:27930341"
FT /id="VAR_016218"
FT VARIANT 206
FT /note="G -> D (in AD3; affects APP processing resulting in
FT increased amyloid-beta 42/amyloid-beta 40 ratio; does not
FT affect NOTCH processing; does not affect endoproteolysis;
FT reduced interaction with PEN2; results in decreased protein
FT levels in the endoplasmic reticulum but increased levels in
FT early endosome; reduced ability to maintain ER calcium
FT homeostasis; dbSNP:rs63750082)"
FT /evidence="ECO:0000269|PubMed:21335660,
FT ECO:0000269|PubMed:25394380, ECO:0000269|PubMed:29175279"
FT /id="VAR_081243"
FT VARIANT 206
FT /note="G -> S (in AD3; results in altered amyloid-beta
FT production and increased amyloid-beta 42/amyloid-beta 40
FT ratio; dbSNP:rs63750569)"
FT /evidence="ECO:0000269|PubMed:11524469,
FT ECO:0000269|PubMed:27930341"
FT /id="VAR_075266"
FT VARIANT 209
FT /note="G -> E (in AD3; unknown pathological significance;
FT dbSNP:rs63750053)"
FT /evidence="ECO:0000269|PubMed:11524469"
FT /id="VAR_075267"
FT VARIANT 209
FT /note="G -> R (in AD3; results in altered amyloid-beta
FT production and increased amyloid-beta 42/amyloid-beta 40
FT ratio; dbSNP:rs63749880)"
FT /evidence="ECO:0000269|PubMed:10447269,
FT ECO:0000269|PubMed:27930341"
FT /id="VAR_009210"
FT VARIANT 209
FT /note="G -> V (in AD3; abolishes protease activity with
FT APP; dbSNP:rs63750053)"
FT /evidence="ECO:0000269|PubMed:27930341,
FT ECO:0000269|PubMed:9521423"
FT /id="VAR_006433"
FT VARIANT 213
FT /note="I -> L (in AD3; increases protease activity with APP
FT resulting in altered amyloid-beta production and increased
FT amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63750861)"
FT /evidence="ECO:0000269|PubMed:11524469,
FT ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:27930341"
FT /id="VAR_075268"
FT VARIANT 213
FT /note="I -> T (in AD3; decreased protease activity with APP
FT resulting in altered amyloid-beta production and increased
FT amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63751309)"
FT /evidence="ECO:0000269|PubMed:18430735,
FT ECO:0000269|PubMed:8733303"
FT /id="VAR_006434"
FT VARIANT 214
FT /note="H -> Y (probable disease-associated variant found in
FT a patient with dementia; dbSNP:rs63751003)"
FT /evidence="ECO:0000269|PubMed:22503161"
FT /id="VAR_070024"
FT VARIANT 217
FT /note="G -> R (in AD3; with unusual amyloid cotton wool
FT plaques; decreased protease activity with APP resulting in
FT altered amyloid-beta production and increased amyloid-beta
FT 42/amyloid-beta 40 ratio; dbSNP:rs267606983)"
FT /evidence="ECO:0000269|PubMed:19667325,
FT ECO:0000269|PubMed:27930341"
FT /id="VAR_081244"
FT VARIANT 219
FT /note="L -> P (in AD3; dbSNP:rs63750761)"
FT /evidence="ECO:0000269|PubMed:10208579"
FT /id="VAR_010126"
FT VARIANT 222
FT /note="Q -> R (in AD3; unknown pathological significance;
FT slightly increased protease activity with APP and slightly
FT increased amyloid-beta 42/amyloid-beta 40 ratio;
FT dbSNP:rs63750009)"
FT /evidence="ECO:0000269|PubMed:11524469,
FT ECO:0000269|PubMed:27930341"
FT /id="VAR_075269"
FT VARIANT 229
FT /note="I -> F (in AD3; decreased protease activity with APP
FT resulting in altered amyloid-beta production and increased
FT amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63749970)"
FT /evidence="ECO:0000269|PubMed:12552037,
FT ECO:0000269|PubMed:27930341"
FT /id="VAR_081245"
FT VARIANT 231
FT /note="A -> T (in AD3; decreased protease activity with APP
FT resulting in altered amyloid-beta production and increased
FT amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63749836)"
FT /evidence="ECO:0000269|PubMed:10441572,
FT ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:27930341,
FT ECO:0000269|PubMed:8634712"
FT /id="VAR_006435"
FT VARIANT 231
FT /note="A -> V (in AD3; results in altered amyloid-beta
FT production and increased amyloid-beta 42/amyloid-beta 40
FT ratio; dbSNP:rs63750799)"
FT /evidence="ECO:0000269|PubMed:16752394,
FT ECO:0000269|PubMed:9384602"
FT /id="VAR_006436"
FT VARIANT 233
FT /note="M -> L (in AD3; slightly decreased protease activity
FT with APP resulting in altered amyloid-beta production and
FT mildly increased amyloid-beta 42/amyloid-beta 40 ratio;
FT dbSNP:rs63751287)"
FT /evidence="ECO:0000269|PubMed:10533070,
FT ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:27930341"
FT /id="VAR_009211"
FT VARIANT 233
FT /note="M -> T (in AD3; decreased protease activity with APP
FT resulting in altered amyloid-beta production and increased
FT amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63751024)"
FT /evidence="ECO:0000269|PubMed:10441572,
FT ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:9172170"
FT /id="VAR_006437"
FT VARIANT 235
FT /note="L -> P (in AD3; abolishes protease activity with
FT APP; dbSNP:rs63749835)"
FT /evidence="ECO:0000269|PubMed:10441572,
FT ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:27930341"
FT /id="VAR_006438"
FT VARIANT 235
FT /note="L -> R (in AD3; abolishes protease activity with
FT APP)"
FT /evidence="ECO:0000269|PubMed:21501661,
FT ECO:0000269|PubMed:27930341"
FT /id="VAR_081246"
FT VARIANT 235
FT /note="L -> V (in AD3; reduced APP cleavage resulting in
FT decreased amyloid-beta 42 and amyloid-beta 40 production;
FT no relevant change in amyloid-beta 42/amyloid-beta 40
FT ratio; dbSNP:rs63751130)"
FT /evidence="ECO:0000269|PubMed:12552037,
FT ECO:0000269|PubMed:27930341"
FT /id="VAR_081247"
FT VARIANT 237
FT /note="F -> I (in AD3; disease phenotype includes spastic
FT paraparesis; unknown pathological significance; severe
FT decrease of protease activity with APP; results in
FT decreased amyloid-beta 42 and amyloid-beta 40 production;
FT dbSNP:rs63750858)"
FT /evidence="ECO:0000269|PubMed:11561050,
FT ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:27930341"
FT /id="VAR_081248"
FT VARIANT 237
FT /note="F -> L (in AD3; unknown pathological significance;
FT dbSNP:rs63750858)"
FT /evidence="ECO:0000269|PubMed:12552037"
FT /id="VAR_081249"
FT VARIANT 246
FT /note="A -> E (in AD3; nearly abolishes protease activity
FT with APP; increased amyloid-beta 42/amyloid-beta 40 ratio;
FT no loss of its ability to cleave Ephb2/CTF1;
FT dbSNP:rs63750526)"
FT /evidence="ECO:0000269|PubMed:17428795,
FT ECO:0000269|PubMed:27930341, ECO:0000269|PubMed:7596406"
FT /id="VAR_006439"
FT VARIANT 250
FT /note="L -> S (in AD3; nearly abolishes protease activity
FT with APP; increased amyloid-beta 42/amyloid-beta 40 ratio;
FT dbSNP:rs63751163)"
FT /evidence="ECO:0000269|PubMed:27930341"
FT /id="VAR_006440"
FT VARIANT 260
FT /note="A -> V (in AD3; nearly abolishes protease activity
FT with APP; increased amyloid-beta 42/amyloid-beta 40 ratio;
FT impaired ability to cleave Ephb2/CTF1; dbSNP:rs63751420)"
FT /evidence="ECO:0000269|PubMed:12552037,
FT ECO:0000269|PubMed:17428795, ECO:0000269|PubMed:27930341,
FT ECO:0000269|PubMed:7651536, ECO:0000269|PubMed:9521423"
FT /id="VAR_006441"
FT VARIANT 261
FT /note="V -> F (in AD3; nearly abolishes protease activity
FT with APP; increased amyloid-beta 42/amyloid-beta 40 ratio;
FT dbSNP:rs63750964)"
FT /evidence="ECO:0000269|PubMed:11524469,
FT ECO:0000269|PubMed:26280335, ECO:0000269|PubMed:27930341"
FT /id="VAR_075270"
FT VARIANT 262
FT /note="L -> F (in AD3; decreased protease activity with APP
FT resulting in altered amyloid-beta production and increased
FT amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63750248)"
FT /evidence="ECO:0000269|PubMed:16752394,
FT ECO:0000269|PubMed:27930341"
FT /id="VAR_006442"
FT VARIANT 262
FT /note="L -> V (in AD3)"
FT /evidence="ECO:0000269|PubMed:22503161"
FT /id="VAR_070025"
FT VARIANT 263
FT /note="C -> F (in AD3; results in altered amyloid-beta
FT production and increased amyloid-beta 42/amyloid-beta 40
FT ratio; dbSNP:rs63751102)"
FT /evidence="ECO:0000269|PubMed:12552037,
FT ECO:0000269|PubMed:16752394"
FT /id="VAR_081250"
FT VARIANT 263
FT /note="C -> R (in AD3; decreased protease activity with
FT APP; increased amyloid-beta 42/amyloid-beta 40 ratio;
FT dbSNP:rs63750543)"
FT /evidence="ECO:0000269|PubMed:27930341"
FT /id="VAR_006443"
FT VARIANT 264
FT /note="P -> L (in AD3; decreased protease activity with
FT APP; increased amyloid-beta 42/amyloid-beta 40 ratio;
FT impaired ability to cleave Ephb2/CTF1; dbSNP:rs63750301)"
FT /evidence="ECO:0000269|PubMed:10441572,
FT ECO:0000269|PubMed:17428795, ECO:0000269|PubMed:27930341,
FT ECO:0000269|PubMed:8634712, ECO:0000269|PubMed:9521423"
FT /id="VAR_006444"
FT VARIANT 266
FT /note="G -> S (in AD3; nearly abolishes protease activity
FT with APP; increased amyloid-beta 42/amyloid-beta 40 ratio;
FT dbSNP:rs121917807)"
FT /evidence="ECO:0000269|PubMed:11920851,
FT ECO:0000269|PubMed:27930341"
FT /id="VAR_016219"
FT VARIANT 267
FT /note="P -> S (in AD3; decreased protease activity with
FT APP; increased amyloid-beta 42/amyloid-beta 40 ratio;
FT dbSNP:rs63751229)"
FT /evidence="ECO:0000269|PubMed:27930341,
FT ECO:0000269|PubMed:7550356"
FT /id="VAR_006445"
FT VARIANT 269
FT /note="R -> G (in AD3; decreased protease activity with
FT APP; increased amyloid-beta 42/amyloid-beta 40 ratio;
FT dbSNP:rs63751019)"
FT /evidence="ECO:0000269|PubMed:27930341"
FT /id="VAR_006447"
FT VARIANT 269
FT /note="R -> H (in AD3; dbSNP:rs63750900)"
FT /evidence="ECO:0000269|PubMed:12552037"
FT /id="VAR_006448"
FT VARIANT 271
FT /note="L -> V (in AD3; abolishes protease activity with
FT APP; dbSNP:rs63750886)"
FT /evidence="ECO:0000269|PubMed:12493737,
FT ECO:0000269|PubMed:27930341"
FT /id="VAR_016220"
FT VARIANT 274
FT /note="T -> R (in AD3; unknown pathological significance;
FT abolishes protease activity with APP; dbSNP:rs63750284)"
FT /evidence="ECO:0000269|PubMed:11524469,
FT ECO:0000269|PubMed:27930341"
FT /id="VAR_075271"
FT VARIANT 275
FT /note="A -> V (in AD3; unknown pathological significance;
FT reduced protease activity with APP resulting in reduced
FT amyloid-beta 40 levels but no relevant changes in amyloid-
FT beta 42/amyloid-beta 40 ratio; dbSNP:rs1555355869)"
FT /evidence="ECO:0000269|PubMed:24582897,
FT ECO:0000269|PubMed:27930341"
FT /id="VAR_081251"
FT VARIANT 278
FT /note="R -> I (in AD3; atypical phenotype presenting as
FT language impairment, impaired frontal executive function
FT and relative preservation of memory; severe decrease of APP
FT and Notch proteolysis; dbSNP:rs63749891)"
FT /evidence="ECO:0000269|PubMed:15534260,
FT ECO:0000269|PubMed:23843529"
FT /id="VAR_081252"
FT VARIANT 278
FT /note="R -> T (in AD3; dbSNP:rs63749891)"
FT /evidence="ECO:0000269|PubMed:9172170"
FT /id="VAR_006449"
FT VARIANT 280
FT /note="E -> A (in AD3; strong deposition of amyloid-beta 42
FT is observed in brain regions of AD3 patients; decreased
FT protease activity with APP resulting in altered amyloid-
FT beta production and increased amyloid-beta 42/amyloid-beta
FT 40 ratio; decreased activity for Notch1 cleavage;
FT dbSNP:rs63750231)"
FT /evidence="ECO:0000269|PubMed:11568920,
FT ECO:0000269|PubMed:22461631, ECO:0000269|PubMed:27930341,
FT ECO:0000269|PubMed:28269784, ECO:0000269|PubMed:7550356,
FT ECO:0000269|PubMed:8837617, ECO:0000269|PubMed:9298817"
FT /id="VAR_006450"
FT VARIANT 280
FT /note="E -> G (in AD3; some AD3 patients manifest spastic
FT paraparesis and unusual amyloid plaques with prominent
FT amyloid angiopathy on brain biopsy; decreased protease
FT activity with APP; increased amyloid-beta 42/amyloid-beta
FT 40 ratio; impaired ability to cleave Ephb2/CTF1;
FT dbSNP:rs63750231)"
FT /evidence="ECO:0000269|PubMed:12370477,
FT ECO:0000269|PubMed:17428795, ECO:0000269|PubMed:27930341,
FT ECO:0000269|PubMed:7550356"
FT /id="VAR_006451"
FT VARIANT 282
FT /note="L -> R (in AD3; abolishes protease activity with
FT APP; dbSNP:rs63750050)"
FT /evidence="ECO:0000269|PubMed:10533070,
FT ECO:0000269|PubMed:27930341"
FT /id="VAR_009212"
FT VARIANT 282
FT /note="L -> V (in AD3; results in altered amyloid-beta
FT production and increased amyloid-beta 42/amyloid-beta 40
FT ratio; dbSNP:rs63749937)"
FT /evidence="ECO:0000269|PubMed:11701593,
FT ECO:0000269|PubMed:15122701, ECO:0000269|PubMed:16752394"
FT /id="VAR_081253"
FT VARIANT 285
FT /note="A -> V (in AD3; slightly decreased protease activity
FT with APP and slightly decreased amyloid-beta 42/amyloid-
FT beta 40 ratio; dbSNP:rs63751139)"
FT /evidence="ECO:0000269|PubMed:27930341,
FT ECO:0000269|PubMed:7651536"
FT /id="VAR_006452"
FT VARIANT 286
FT /note="L -> V (in AD3; results in altered amyloid-beta
FT production and increased amyloid-beta 42/amyloid-beta 40
FT ratio; dbSNP:rs63751235)"
FT /evidence="ECO:0000269|PubMed:27930341,
FT ECO:0000269|PubMed:7596406"
FT /id="VAR_006453"
FT VARIANT 289
FT /note="S -> C (in AD3)"
FT /id="VAR_010127"
FT VARIANT 311
FT /note="K -> R (probable disease-associated variant found in
FT patients with late-onset Alzheimer disease; results in
FT altered amyloid-beta production and increased amyloid-beta
FT 42/amyloid-beta 40 ratio; dbSNP:rs115865530)"
FT /evidence="ECO:0000269|PubMed:28269784"
FT /id="VAR_081254"
FT VARIANT 315
FT /note="Y -> C (found in a renal cell carcinoma sample;
FT somatic mutation)"
FT /evidence="ECO:0000269|PubMed:21248752"
FT /id="VAR_064747"
FT VARIANT 318
FT /note="E -> G (in dbSNP:rs17125721)"
FT /evidence="ECO:0000269|PubMed:10441572,
FT ECO:0000269|PubMed:10533070, ECO:0000269|PubMed:10631141,
FT ECO:0000269|PubMed:11524469, ECO:0000269|PubMed:11568920,
FT ECO:0000269|PubMed:12552037, ECO:0000269|PubMed:18485326,
FT ECO:0000269|PubMed:9384602, ECO:0000269|PubMed:9851443,
FT ECO:0000269|PubMed:9851450, ECO:0000269|PubMed:9915968"
FT /id="VAR_006454"
FT VARIANT 333
FT /note="D -> G (in CMD1U; results in slightly decreased
FT protease activity with APP and slightly decreased amyloid-
FT beta 42/amyloid-beta 40 ratio; dbSNP:rs121917809)"
FT /evidence="ECO:0000269|PubMed:17186461,
FT ECO:0000269|PubMed:27930341"
FT /id="VAR_064902"
FT VARIANT 352
FT /note="R -> RR (in AD3; unknown pathological significance)"
FT /evidence="ECO:0000269|PubMed:11524469"
FT /id="VAR_075272"
FT VARIANT 354
FT /note="T -> I (in AD3; unknown pathological significance;
FT results in decreased protease activity with APP and
FT decreased amyloid-beta 42/amyloid-beta 40 ratio;
FT dbSNP:rs63751164)"
FT /evidence="ECO:0000269|PubMed:11524469,
FT ECO:0000269|PubMed:27930341"
FT /id="VAR_075273"
FT VARIANT 358
FT /note="R -> Q (in AD3; unknown pathological significance;
FT results in altered amyloid-beta production and increased
FT amyloid-beta 42/amyloid-beta 40 ratio; dbSNP:rs63751174)"
FT /evidence="ECO:0000269|PubMed:11524469,
FT ECO:0000269|PubMed:27930341"
FT /id="VAR_075274"
FT VARIANT 365
FT /note="S -> Y (in AD3; unknown pathological significance;
FT dbSNP:rs63750941)"
FT /evidence="ECO:0000269|PubMed:11524469"
FT /id="VAR_075275"
FT VARIANT 377
FT /note="R -> M (in AD3; unknown pathological significance)"
FT /evidence="ECO:0000269|PubMed:12552037"
FT /id="VAR_081255"
FT VARIANT 378
FT /note="G -> E (in AD3; decreased protease activity with
FT APP; results in altered amyloid-beta production and
FT increased amyloid-beta 42/amyloid-beta 40 ratio)"
FT /evidence="ECO:0000269|PubMed:10200054,
FT ECO:0000269|PubMed:27930341"
FT /id="VAR_006455"
FT VARIANT 378
FT /note="G -> V (in AD3; abolishes protease activity with
FT APP; dbSNP:rs63750323)"
FT /evidence="ECO:0000269|PubMed:12552037,
FT ECO:0000269|PubMed:27073747, ECO:0000269|PubMed:27930341"
FT /id="VAR_081256"
FT VARIANT 381
FT /note="L -> F (in AD3; dbSNP:rs63750687)"
FT /evidence="ECO:0000269|PubMed:24121961"
FT /id="VAR_081257"
FT VARIANT 381
FT /note="L -> V (in AD3; results in altered amyloid-beta
FT production and increased amyloid-beta 42/amyloid-beta 40
FT ratio; dbSNP:rs63750687)"
FT /evidence="ECO:0000269|PubMed:19797784,
FT ECO:0000269|PubMed:27930341"
FT /id="VAR_081258"
FT VARIANT 384
FT /note="G -> A (in AD3; results in reduced APP and Notch
FT proteolysis; results in altered amyloid-beta production and
FT increased amyloid-beta 42/amyloid-beta 40 ratio;
FT dbSNP:rs63750646)"
FT /evidence="ECO:0000269|PubMed:16752394,
FT ECO:0000269|PubMed:23843529, ECO:0000269|PubMed:27930341,
FT ECO:0000269|PubMed:8634711"
FT /id="VAR_006456"
FT VARIANT 390
FT /note="S -> I (in AD3; abolishes protease activity with
FT APP; dbSNP:rs63750883)"
FT /evidence="ECO:0000269|PubMed:10441572,
FT ECO:0000269|PubMed:27930341"
FT /id="VAR_010128"
FT VARIANT 392
FT /note="L -> V (in AD3; results in reduced APP and Notch
FT proteolysis; results in altered amyloid-beta production and
FT increased amyloid-beta 42/amyloid-beta 40 ratio;
FT dbSNP:rs63751416)"
FT /evidence="ECO:0000269|PubMed:10441572,
FT ECO:0000269|PubMed:23843529, ECO:0000269|PubMed:27930341,
FT ECO:0000269|PubMed:7651536, ECO:0000269|PubMed:8634712"
FT /id="VAR_006457"
FT VARIANT 394
FT /note="G -> V (in AD3; unknown pathological significance;
FT abolishes protease activity with APP; dbSNP:rs63750929)"
FT /evidence="ECO:0000269|PubMed:11524469,
FT ECO:0000269|PubMed:27930341"
FT /id="VAR_075276"
FT VARIANT 396
FT /note="A -> T (in AD3; unknown pathological significance;
FT decreased protease activity with APP; results in altered
FT amyloid-beta production and increased amyloid-beta 42/
FT amyloid-beta 40 ratio)"
FT /evidence="ECO:0000269|PubMed:27930341"
FT /id="VAR_070026"
FT VARIANT 405
FT /note="N -> S (in AD3; unknown pathological significance;
FT decreased protease activity with APP; dbSNP:rs63751254)"
FT /evidence="ECO:0000269|PubMed:10644793,
FT ECO:0000269|PubMed:27930341"
FT /id="VAR_010129"
FT VARIANT 408
FT /note="I -> T (in AD3; dbSNP:rs906454643)"
FT /evidence="ECO:0000269|PubMed:26549787"
FT /id="VAR_075277"
FT VARIANT 409
FT /note="A -> T (in AD3; unknown pathological significance;
FT decreased protease activity with APP; dbSNP:rs63750227)"
FT /evidence="ECO:0000269|PubMed:10533070,
FT ECO:0000269|PubMed:27930341"
FT /id="VAR_009213"
FT VARIANT 410
FT /note="C -> Y (in AD3; results in reduced APP and Notch
FT proteolysis; dbSNP:rs661)"
FT /evidence="ECO:0000269|PubMed:10441572,
FT ECO:0000269|PubMed:23843529, ECO:0000269|PubMed:27930341,
FT ECO:0000269|PubMed:8634712, ECO:0000269|PubMed:9521423"
FT /id="VAR_006458"
FT VARIANT 417
FT /note="G -> A (in AD3; unknown pathological significance)"
FT /evidence="ECO:0000269|PubMed:30180983"
FT /id="VAR_081259"
FT VARIANT 418
FT /note="L -> F (in AD3; unknown pathological significance;
FT nearly abolishes protease activity with APP;
FT dbSNP:rs63751316)"
FT /evidence="ECO:0000269|PubMed:11524469,
FT ECO:0000269|PubMed:27930341"
FT /id="VAR_075278"
FT VARIANT 426
FT /note="A -> P (in AD3; unknown pathological significance;
FT slightly decreased protease activity with APP;
FT dbSNP:rs63751223)"
FT /evidence="ECO:0000269|PubMed:27930341,
FT ECO:0000269|PubMed:9521423"
FT /id="VAR_006459"
FT VARIANT 431
FT /note="A -> E (in AD3; decreased protease activity with
FT APP; results in altered amyloid-beta production and
FT increased amyloid-beta 42/amyloid-beta 40 ratio;
FT dbSNP:rs63750083)"
FT /evidence="ECO:0000269|PubMed:11524469,
FT ECO:0000269|PubMed:16628450, ECO:0000269|PubMed:16897084,
FT ECO:0000269|PubMed:27930341, ECO:0000269|Ref.93"
FT /id="VAR_025605"
FT VARIANT 435
FT /note="L -> F (in AD3; with unusual amyloid cotton wool
FT plaques; almost abolishes gamma-secretase activity; no
FT endoproteolytic cleavage; no APP nor NOTCH1 processing; no
FT detectable amyloid-beta; dbSNP:rs63750001)"
FT /evidence="ECO:0000269|PubMed:11524469,
FT ECO:0000269|PubMed:16305624, ECO:0000269|PubMed:20460383,
FT ECO:0000269|PubMed:23843529, ECO:0000269|PubMed:27930341"
FT /id="VAR_075280"
FT VARIANT 436
FT /note="P -> Q (in AD3; severe decrease of protease activity
FT with APP; dbSNP:rs121917808)"
FT /evidence="ECO:0000269|PubMed:22529981,
FT ECO:0000269|PubMed:9831473"
FT /id="VAR_006460"
FT VARIANT 436
FT /note="P -> S (in AD3; partially abolishes gamma-secretase
FT activity; results in altered amyloid-beta production and
FT increased amyloid-beta 42/amyloid-beta 40 ratio;
FT dbSNP:rs63749925)"
FT /evidence="ECO:0000269|PubMed:10090481,
FT ECO:0000269|PubMed:21248752, ECO:0000269|PubMed:27930341"
FT /id="VAR_008141"
FT VARIANT 439
FT /note="I -> V (in AD3; unknown pathological significance;
FT no significant change of protease activity with APP;
FT dbSNP:rs63750249)"
FT /evidence="ECO:0000269|PubMed:11524469,
FT ECO:0000269|PubMed:27930341"
FT /id="VAR_075282"
FT MUTAGEN 66..72
FT /note="Missing: No effect on interaction with GFAP."
FT /evidence="ECO:0000269|PubMed:12058025"
FT MUTAGEN 76..77
FT /note="KY->AA: No effect on interaction with GFAP."
FT /evidence="ECO:0000269|PubMed:12058025"
FT MUTAGEN 82..83
FT /note="VI->EE: Loss of interaction with GFAP."
FT /evidence="ECO:0000269|PubMed:12058025"
FT MUTAGEN 82
FT /note="V->K,E: Loss of interaction with GFAP."
FT /evidence="ECO:0000269|PubMed:12058025"
FT MUTAGEN 84..85
FT /note="ML->EE: Loss of interaction with GFAP."
FT /evidence="ECO:0000269|PubMed:12058025"
FT MUTAGEN 99
FT /note="T->A: Nearly abolishes protease activity with APP.
FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro."
FT /evidence="ECO:0000269|PubMed:27930341"
FT MUTAGEN 105
FT /note="F->I: Nearly abolishes protease activity with APP.
FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro."
FT /evidence="ECO:0000269|PubMed:27930341"
FT MUTAGEN 108
FT /note="R->Q: Nearly abolishes protease activity with APP."
FT /evidence="ECO:0000269|PubMed:27930341"
FT MUTAGEN 112
FT /note="Q->C: Formation of an artifactual disulfide bond
FT with a substrate protein."
FT /evidence="ECO:0000269|PubMed:30598546,
FT ECO:0000269|PubMed:30630874"
FT MUTAGEN 113
FT /note="L->Q: Severe decrease of protease activity with APP.
FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro."
FT /evidence="ECO:0000269|PubMed:27930341"
FT MUTAGEN 117
FT /note="P->A: Nearly abolishes protease activity with APP.
FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro."
FT /evidence="ECO:0000269|PubMed:27930341"
FT MUTAGEN 123
FT /note="E->K: Nearly abolishes protease activity with APP.
FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro."
FT /evidence="ECO:0000269|PubMed:27930341"
FT MUTAGEN 131
FT /note="H->R: Severe decrease of protease activity with
FT APP."
FT /evidence="ECO:0000269|PubMed:27930341"
FT MUTAGEN 136
FT /note="A->G: Decreased protease activity with APP."
FT /evidence="ECO:0000269|PubMed:27930341"
FT MUTAGEN 143
FT /note="I->V: Increased amyloid-beta 42/amyloid-beta 40
FT ratio in vitro."
FT /evidence="ECO:0000269|PubMed:27930341"
FT MUTAGEN 150
FT /note="L->P: Nearly abolishes protease activity with APP."
FT /evidence="ECO:0000269|PubMed:27930341"
FT MUTAGEN 165
FT /note="W->G: Decreased protease activity with APP.
FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro."
FT /evidence="ECO:0000269|PubMed:27930341"
FT MUTAGEN 168
FT /note="I->T: Nearly abolishes protease activity with APP."
FT /evidence="ECO:0000269|PubMed:27930341"
FT MUTAGEN 176
FT /note="F->L: Nearly abolishes protease activity with APP."
FT /evidence="ECO:0000269|PubMed:27930341"
FT MUTAGEN 184
FT /note="E->G: Nearly abolishes protease activity with APP.
FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro."
FT /evidence="ECO:0000269|PubMed:27930341"
FT MUTAGEN 202
FT /note="I->F: Nearly abolishes protease activity with APP."
FT /evidence="ECO:0000269|PubMed:26280335,
FT ECO:0000269|PubMed:27930341"
FT MUTAGEN 212
FT /note="S->Y: Nearly abolishes protease activity with APP."
FT /evidence="ECO:0000269|PubMed:27930341"
FT MUTAGEN 214
FT /note="H->D: Nearly abolishes protease activity with APP.
FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro."
FT /evidence="ECO:0000269|PubMed:27930341"
FT MUTAGEN 219
FT /note="L->F: Decreased protease activity with APP.
FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro."
FT /evidence="ECO:0000269|PubMed:27930341"
FT MUTAGEN 223
FT /note="Q->R: Abolishes protease activity with APP."
FT /evidence="ECO:0000269|PubMed:27930341"
FT MUTAGEN 226
FT /note="L->F: Increases protease activity with APP."
FT /evidence="ECO:0000269|PubMed:26280335,
FT ECO:0000269|PubMed:27930341"
FT MUTAGEN 230
FT /note="S->I: Abolishes protease activity with APP."
FT /evidence="ECO:0000269|PubMed:27930341"
FT MUTAGEN 238
FT /note="I->M: Abolishes protease activity with APP."
FT /evidence="ECO:0000269|PubMed:27930341"
FT MUTAGEN 239
FT /note="K->N: Abolishes protease activity with APP."
FT /evidence="ECO:0000269|PubMed:27930341"
FT MUTAGEN 245
FT /note="T->P: Abolishes protease activity with APP."
FT /evidence="ECO:0000269|PubMed:27930341"
FT MUTAGEN 248
FT /note="L->R: Nearly abolishes protease activity with APP.
FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro."
FT /evidence="ECO:0000269|PubMed:26280335,
FT ECO:0000269|PubMed:27930341"
FT MUTAGEN 256
FT /note="Y->F: Alters gamma-secretase cleavage specificity.
FT Increased production of amyloid-beta protein 42. No effect
FT on enzymatic activity."
FT /evidence="ECO:0000269|PubMed:15341515"
FT MUTAGEN 256
FT /note="Y->S: Nearly abolishes protease activity with APP.
FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro."
FT /evidence="ECO:0000269|PubMed:27930341"
FT MUTAGEN 257
FT /note="D->A: Impaired ability to cleave Ephb2/CTF1."
FT /evidence="ECO:0000269|PubMed:17428795"
FT MUTAGEN 257
FT /note="D->A: Loss of endoproteolytic cleavage. Severe
FT decrease of protease activity with APP. Reduces production
FT of amyloid-beta. Reduces production of NICD in NOTCH1
FT processing."
FT /evidence="ECO:0000269|PubMed:10206644,
FT ECO:0000269|PubMed:10899933, ECO:0000269|PubMed:15341515,
FT ECO:0000269|PubMed:22529981"
FT MUTAGEN 257
FT /note="D->E: Abolishes gamma-secretase activity. Reduces
FT production of amyloid-beta in APP processing. Accumulation
FT of full-length PS1. Loss of binding of transition state
FT analog gamma-secretase inhibitor."
FT /evidence="ECO:0000269|PubMed:10206644,
FT ECO:0000269|PubMed:10899933, ECO:0000269|PubMed:15341515"
FT MUTAGEN 272
FT /note="V->A: Increased amyloid-beta 42/amyloid-beta 40
FT ratio in vitro."
FT /evidence="ECO:0000269|PubMed:27930341"
FT MUTAGEN 273
FT /note="E->A: Decreased protease activity with APP.
FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro."
FT /evidence="ECO:0000269|PubMed:27930341"
FT MUTAGEN 278
FT /note="R->K: Nearly abolishes protease activity with APP.
FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro."
FT /evidence="ECO:0000269|PubMed:27930341"
FT MUTAGEN 284
FT /note="P->S: No significant change of protease activity
FT with APP."
FT /evidence="ECO:0000269|PubMed:27930341"
FT MUTAGEN 286
FT /note="L->A,E,P,Q,R,W: Increases production of amyloid-beta
FT in APP processing."
FT /evidence="ECO:0000269|PubMed:10811883"
FT MUTAGEN 286
FT /note="L->E,R: Reduces production of NICD in NOTCH1
FT processing."
FT /evidence="ECO:0000269|PubMed:10811883"
FT MUTAGEN 288..290
FT /note="Missing: Loss of NOTCH1 and APP C83 cleavage."
FT /evidence="ECO:0000269|PubMed:30598546,
FT ECO:0000269|PubMed:30630874"
FT MUTAGEN 291
FT /note="T->P: Abolishes protease activity with APP."
FT /evidence="ECO:0000269|PubMed:27930341"
FT MUTAGEN 292
FT /note="M->D: Loss of endoproteolytic cleavage."
FT /evidence="ECO:0000269|PubMed:10545183"
FT MUTAGEN 310
FT /note="S->A: Abolishes PKA-mediated phosphorylation; no
FT effect on caspase-mediated cleavage."
FT /evidence="ECO:0000269|PubMed:14576165"
FT MUTAGEN 345
FT /note="D->N: Abolishes caspase cleavage."
FT /evidence="ECO:0000269|PubMed:9485372"
FT MUTAGEN 346
FT /note="S->A: Abolishes PKC-mediated phosphorylation; no
FT effect on PKA-mediated phosphorylation."
FT /evidence="ECO:0000269|PubMed:14576165"
FT MUTAGEN 346
FT /note="S->E: Inhibits caspase-mediated cleavage. Modulates
FT progression of apoptosis."
FT /evidence="ECO:0000269|PubMed:14576165"
FT MUTAGEN 352
FT /note="R->C: Decreased protease activity with APP."
FT /evidence="ECO:0000269|PubMed:27930341"
FT MUTAGEN 365
FT /note="S->A: Slightly increased protease activity with
FT APP."
FT /evidence="ECO:0000269|PubMed:27930341"
FT MUTAGEN 373
FT /note="D->N: No effect on caspase cleavage."
FT /evidence="ECO:0000269|PubMed:9485372"
FT MUTAGEN 377..381
FT /note="Missing: Loss of NOTCH1 and APP C83 cleavage."
FT /evidence="ECO:0000269|PubMed:30598546,
FT ECO:0000269|PubMed:30630874"
FT MUTAGEN 377
FT /note="R->W: Nearly abolishes protease activity with APP."
FT /evidence="ECO:0000269|PubMed:27930341"
FT MUTAGEN 385
FT /note="D->A: Loss of endoproteolytic cleavage. Severe
FT decrease of protease activity with APP. Reduces production
FT of amyloid-beta. Loss of NOTCH1 cleavage. Disassembly of
FT the N-cadherin/PS1 complex at the cell surface. Impairs
FT CDH2 processing."
FT /evidence="ECO:0000269|PubMed:10206644,
FT ECO:0000269|PubMed:10899933, ECO:0000269|PubMed:14515347,
FT ECO:0000269|PubMed:15341515, ECO:0000269|PubMed:22529981,
FT ECO:0000269|PubMed:30598546, ECO:0000269|PubMed:30630874,
FT ECO:0000269|PubMed:9485372"
FT MUTAGEN 385
FT /note="D->E: Abolishes gamma-secretase activity. Reduces
FT production of amyloid-beta in APP processing. Accumulation
FT of full-length PS1. Loss of binding of transition state
FT analog gamma-secretase inhibitor."
FT /evidence="ECO:0000269|PubMed:10206644,
FT ECO:0000269|PubMed:10899933, ECO:0000269|PubMed:14515347,
FT ECO:0000269|PubMed:15341515, ECO:0000269|PubMed:9485372"
FT MUTAGEN 385
FT /note="D->N: No effect on caspase cleavage."
FT /evidence="ECO:0000269|PubMed:10206644,
FT ECO:0000269|PubMed:10899933, ECO:0000269|PubMed:14515347,
FT ECO:0000269|PubMed:15341515, ECO:0000269|PubMed:9485372"
FT MUTAGEN 386
FT /note="F->S: Nearly abolishes protease activity with APP.
FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro."
FT /evidence="ECO:0000269|PubMed:27930341"
FT MUTAGEN 389
FT /note="Y->F: Alters gamma-secretase cleavage specificity.
FT Increased production of amyloid-beta protein 42. No effect
FT on enzymatic activity."
FT /evidence="ECO:0000269|PubMed:15341515"
FT MUTAGEN 391
FT /note="V->F: Decreased protease activity with APP."
FT /evidence="ECO:0000269|PubMed:27930341"
FT MUTAGEN 412
FT /note="V->I: Abolishes protease activity with APP."
FT /evidence="ECO:0000269|PubMed:27930341"
FT MUTAGEN 420
FT /note="L->R: Decreased protease activity with APP.
FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro."
FT /evidence="ECO:0000269|PubMed:27930341"
FT MUTAGEN 424
FT /note="L->V: Increases protease activity with APP."
FT /evidence="ECO:0000269|PubMed:26280335,
FT ECO:0000269|PubMed:27930341"
FT MUTAGEN 432..434
FT /note="Missing: Loss of NOTCH1 and APP C83 cleavage."
FT /evidence="ECO:0000269|PubMed:30598546,
FT ECO:0000269|PubMed:30630874"
FT MUTAGEN 432
FT /note="L->P: Loss of NOTCH1 and APP C83 cleavage."
FT /evidence="ECO:0000269|PubMed:30598546,
FT ECO:0000269|PubMed:30630874"
FT MUTAGEN 433
FT /note="P->A: No effect on endoproteolytic cleavage. No
FT effect on APP nor NOTCH1 processing. Slightly increased
FT amyloid-beta protein 42/40 ratio."
FT /evidence="ECO:0000269|PubMed:16305624"
FT MUTAGEN 433
FT /note="P->D,F,L,N,V: No endoproteolytic cleavage; no APP,
FT nor NOTCH1 processing. No detectable amyloid-beta."
FT /evidence="ECO:0000269|PubMed:16305624,
FT ECO:0000269|PubMed:20460383"
FT MUTAGEN 433
FT /note="P->G: Very little endoproteolysis. Little APP
FT processing. No NOTCH1 processing. Very low levels amyloid-
FT beta protein 40 and no detectable amyloid-beta protein 42."
FT /evidence="ECO:0000269|PubMed:16305624"
FT MUTAGEN 434
FT /note="A->C: Some loss of endoproteolytic cleavage. Some
FT loss of APP and NOTCH1 processing. 6 to 13-fold increase in
FT amyloid-beta protein 42/40 ratio."
FT /evidence="ECO:0000269|PubMed:16305624,
FT ECO:0000269|PubMed:27930341"
FT MUTAGEN 434
FT /note="A->D,I,L,V: No endoproteolytic cleavage. No APP nor
FT NOTCH1 processing. No detectable amyloid-beta."
FT /evidence="ECO:0000269|PubMed:16305624"
FT MUTAGEN 434
FT /note="A->G: No effect on endoproteolytic cleavage. No
FT effect on APP nor NOTCH1 processing. Reduced amyloid-beta
FT protein 42/40 ratio."
FT /evidence="ECO:0000269|PubMed:16305624"
FT MUTAGEN 435
FT /note="L->A: No effect on endoproteolytic cleavage. No
FT effect on APP processing. Impaired NOTCH1 processing.
FT Greatly reduced amyloid-beta protein 42/40 ratio."
FT /evidence="ECO:0000269|PubMed:16305624"
FT MUTAGEN 435
FT /note="L->G: Greatly reduced endoproteolytic cleavage. Very
FT little APP and NOTCH1 processing. Very low levels of
FT amyloid-beta protein 40 and no detectable amyloid-beta
FT protein 42."
FT /evidence="ECO:0000269|PubMed:16305624"
FT MUTAGEN 435
FT /note="L->I: No effect on endoproteolytic cleavage. No
FT effect on APP nor NOTCH1 processing."
FT /evidence="ECO:0000269|PubMed:16305624"
FT MUTAGEN 435
FT /note="L->R: No endoproteolytic cleavage; no APP, nor
FT NOTCH1 processing. No detectable amyloid-beta."
FT /evidence="ECO:0000269|PubMed:20460383"
FT MUTAGEN 435
FT /note="L->V: No effect on endoproteolytic cleavage. No
FT effect on APP processing. Impaired NOTCH1 processing. Some
FT increase in amyloid-beta protein 42/40 ratio."
FT /evidence="ECO:0000269|PubMed:16305624"
FT MUTAGEN 437
FT /note="I->V: Decreased protease activity with APP.
FT Increased amyloid-beta 42/amyloid-beta 40 ratio in vitro."
FT /evidence="ECO:0000269|PubMed:27930341"
FT CONFLICT 128
FT /note="R -> G (in Ref. 7; AAL16811)"
FT /evidence="ECO:0000305"
FT HELIX 74..102
FT /evidence="ECO:0007829|PDB:6IYC"
FT HELIX 105..107
FT /evidence="ECO:0007829|PDB:6IYC"
FT STRAND 114..116
FT /evidence="ECO:0007829|PDB:6LQG"
FT STRAND 120..123
FT /evidence="ECO:0007829|PDB:6IYC"
FT HELIX 125..155
FT /evidence="ECO:0007829|PDB:6IYC"
FT HELIX 159..175
FT /evidence="ECO:0007829|PDB:6IYC"
FT HELIX 177..188
FT /evidence="ECO:0007829|PDB:6IYC"
FT HELIX 195..214
FT /evidence="ECO:0007829|PDB:6IYC"
FT HELIX 219..239
FT /evidence="ECO:0007829|PDB:6IYC"
FT HELIX 243..262
FT /evidence="ECO:0007829|PDB:6IYC"
FT STRAND 263..266
FT /evidence="ECO:0007829|PDB:6IDF"
FT HELIX 269..277
FT /evidence="ECO:0007829|PDB:6IYC"
FT STRAND 278..280
FT /evidence="ECO:0007829|PDB:6IDF"
FT STRAND 284..289
FT /evidence="ECO:0007829|PDB:6IYC"
FT HELIX 293..299
FT /evidence="ECO:0007829|PDB:2KR6"
FT STRAND 341..345
FT /evidence="ECO:0007829|PDB:2KR6"
FT HELIX 356..368
FT /evidence="ECO:0007829|PDB:2KR6"
FT STRAND 378..382
FT /evidence="ECO:0007829|PDB:6IYC"
FT HELIX 383..398
FT /evidence="ECO:0007829|PDB:6IYC"
FT STRAND 401..404
FT /evidence="ECO:0007829|PDB:6IYC"
FT HELIX 405..428
FT /evidence="ECO:0007829|PDB:6IYC"
FT STRAND 432..435
FT /evidence="ECO:0007829|PDB:6IYC"
FT HELIX 438..449
FT /evidence="ECO:0007829|PDB:6IYC"
FT TURN 450..452
FT /evidence="ECO:0007829|PDB:6IYC"
FT HELIX 453..463
FT /evidence="ECO:0007829|PDB:6IYC"
SQ SEQUENCE 467 AA; 52668 MW; 5E0F451EF82BCF20 CRC64;
MTELPAPLSY FQNAQMSEDN HLSNTVRSQN DNRERQEHND RRSLGHPEPL SNGRPQGNSR
QVVEQDEEED EELTLKYGAK HVIMLFVPVT LCMVVVVATI KSVSFYTRKD GQLIYTPFTE
DTETVGQRAL HSILNAAIMI SVIVVMTILL VVLYKYRCYK VIHAWLIISS LLLLFFFSFI
YLGEVFKTYN VAVDYITVAL LIWNFGVVGM ISIHWKGPLR LQQAYLIMIS ALMALVFIKY
LPEWTAWLIL AVISVYDLVA VLCPKGPLRM LVETAQERNE TLFPALIYSS TMVWLVNMAE
GDPEAQRRVS KNSKYNAEST ERESQDTVAE NDDGGFSEEW EAQRDSHLGP HRSTPESRAA
VQELSSSILA GEDPEERGVK LGLGDFIFYS VLVGKASATA SGDWNTTIAC FVAILIGLCL
TLLLLAIFKK ALPALPISIT FGLVFYFATD YLVQPFMDQL AFHQFYI
