ASM_HUMAN
ID ASM_HUMAN Reviewed; 631 AA.
AC P17405; A8K8M3; E9PKS3; P17406; Q13811; Q16837; Q16841;
DT 01-AUG-1990, integrated into UniProtKB/Swiss-Prot.
DT 12-SEP-2018, sequence version 5.
DT 03-AUG-2022, entry version 225.
DE RecName: Full=Sphingomyelin phosphodiesterase {ECO:0000305};
DE EC=3.1.4.12 {ECO:0000269|PubMed:15877209, ECO:0000269|PubMed:1718266, ECO:0000269|PubMed:1840600, ECO:0000269|PubMed:18815062, ECO:0000269|PubMed:25339683, ECO:0000269|PubMed:26084044, ECO:0000269|PubMed:8702487};
DE EC=3.1.4.3 {ECO:0000269|PubMed:25339683};
DE AltName: Full=Acid sphingomyelinase {ECO:0000303|PubMed:25339683, ECO:0000303|PubMed:27349982, ECO:0000303|PubMed:33163980};
DE Short=aSMase;
DE Flags: Precursor;
GN Name=SMPD1 {ECO:0000312|HGNC:HGNC:11120};
GN Synonyms=ASM {ECO:0000303|PubMed:25339683};
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 [MRNA], FUNCTION, CATALYTIC ACTIVITY, ALTERNATIVE
RP SPLICING, AND VARIANTS 48-ALA-LEU-49 DEL; ILE-324 AND ARG-508.
RX PubMed=1840600; DOI=10.1016/s0021-9258(18)93007-3;
RA Schuchman E.H., Suchi M., Takahashi T., Sandhoff K., Desnick R.J.;
RT "Human acid sphingomyelinase. Isolation, nucleotide sequence and expression
RT of the full-length and alternatively spliced cDNAs.";
RL J. Biol. Chem. 266:8531-8539(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS 48-ALA-LEU-49 DEL AND
RP ARG-508.
RX PubMed=1292508; DOI=10.1515/bchm3.1992.373.2.1233;
RA Newrzella D., Stoffel W.;
RT "Molecular cloning of the acid sphingomyelinase of the mouse and the
RT organization and complete nucleotide sequence of the gene.";
RL Biol. Chem. Hoppe-Seyler 373:1233-1238(1992).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS 36-VAL--LEU-39 DEL AND
RP ALA-36.
RX PubMed=1740330; DOI=10.1016/0888-7543(92)90366-z;
RA Schuchman E.H., Levran O., Pereira L.V., Desnick R.J.;
RT "Structural organization and complete nucleotide sequence of the gene
RT encoding human acid sphingomyelinase (SMPD1).";
RL Genomics 12:197-205(1992).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANTS 36-VAL--LEU-39 DEL; 48-ALA-LEU-49
RP DEL AND ARG-159.
RX PubMed=8407868; DOI=10.1093/oxfordjournals.jbchem.a124131;
RA Ida H., Rennert O.M., Eto Y., Chan W.Y.;
RT "Cloning of a human acid sphingomyelinase cDNA with a new mutation that
RT renders the enzyme inactive.";
RL J. Biochem. 114:15-20(1993).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4), AND VARIANTS
RP 48-ALA-LEU-49 DEL AND ARG-508.
RC TISSUE=Testis;
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 [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16554811; DOI=10.1038/nature04632;
RA Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K.,
RA Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T.,
RA Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G.,
RA Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C.,
RA Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A.,
RA Hattori M., Rogers J., Lander E.S., Sakaki Y.;
RT "Human chromosome 11 DNA sequence and analysis including novel gene
RT identification.";
RL Nature 440:497-500(2006).
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 130-631, PARTIAL PROTEIN SEQUENCE,
RP ALTERNATIVE SPLICING, AND VARIANTS ILE-324 AND ARG-508.
RC TISSUE=Fibroblast;
RX PubMed=2555181; DOI=10.1002/j.1460-2075.1989.tb08382.x;
RA Quintern L.E., Schuchman E.H., Levran O., Suchi M., Ferlinz K., Reinke H.,
RA Sandhoff K., Desnick R.J.;
RT "Isolation of cDNA clones encoding human acid sphingomyelinase: occurrence
RT of alternatively processed transcripts.";
RL EMBO J. 8:2469-2473(1989).
RN [8]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=8706124; DOI=10.1016/s0092-8674(00)80091-4;
RA Santana P., Pena L.A., Haimovitz-Friedman A., Martin S., Green D.,
RA McLoughlin M., Cordon-Cardo C., Schuchman E.H., Fuks Z., Kolesnick R.;
RT "Acid sphingomyelinase-deficient human lymphoblasts and mice are defective
RT in radiation-induced apoptosis.";
RL Cell 86:189-199(1996).
RN [9]
RP CATALYTIC ACTIVITY, COFACTOR, AND SUBCELLULAR LOCATION.
RX PubMed=8702487; DOI=10.1074/jbc.271.31.18431;
RA Schissel S.L., Schuchman E.H., Williams K.J., Tabas I.;
RT "Zn2+-stimulated sphingomyelinase is secreted by many cell types and is a
RT product of the acid sphingomyelinase gene.";
RL J. Biol. Chem. 271:18431-18436(1996).
RN [10]
RP GLYCOSYLATION AT ASN-88; ASN-177; ASN-337; ASN-397 AND ASN-522, MUTAGENESIS
RP OF ASN-88; ASN-177; ASN-337; ASN-397; ASN-505 AND ASN-522, SUBCELLULAR
RP LOCATION, PROTEOLYTIC CLEAVAGE, AND PHOSPHORYLATION.
RX PubMed=9030779; DOI=10.1111/j.1432-1033.1997.511_1a.x;
RA Ferlinz K., Hurwitz R., Moczall H., Lansmann S., Schuchman E.H.,
RA Sandhoff K.;
RT "Functional characterization of the N-glycosylation sites of human acid
RT sphingomyelinase by site-directed mutagenesis.";
RL Eur. J. Biochem. 243:511-517(1997).
RN [11]
RP FUNCTION, AND FUNCTION (MICROBIAL INFECTION).
RX PubMed=9393854; DOI=10.1016/s0092-8674(00)80448-1;
RA Grassme H., Gulbins E., Brenner B., Ferlinz K., Sandhoff K., Harzer K.,
RA Lang F., Meyer T.F.;
RT "Acidic sphingomyelinase mediates entry of N. gonorrhoeae into
RT nonphagocytic cells.";
RL Cell 91:605-615(1997).
RN [12]
RP DISULFIDE BONDS, AND IDENTIFICATION BY MASS SPECTROMETRY.
RX PubMed=12631268; DOI=10.1046/j.1432-1033.2003.03435.x;
RA Lansmann S., Schuette C.G., Bartelsen O., Hoernschemeyer J., Linke T.,
RA Weisgerber J., Sandhoff K.;
RT "Human acid sphingomyelinase.";
RL Eur. J. Biochem. 270:1076-1088(2003).
RN [13]
RP FUNCTION, SUBCELLULAR LOCATION, ACTIVITY REGULATION (MICROBIAL INFECTION),
RP AND CATALYTIC ACTIVITY.
RX PubMed=12563314; DOI=10.1038/nm823;
RA Grassme H., Jendrossek V., Riehle A., von Kuerthy G., Berger J.,
RA Schwarz H., Weller M., Kolesnick R., Gulbins E.;
RT "Host defense against Pseudomonas aeruginosa requires ceramide-rich
RT membrane rafts.";
RL Nat. Med. 9:322-330(2003).
RN [14]
RP SUBCELLULAR LOCATION, FUNCTION, AND INTERACTION WITH SORT1.
RX PubMed=16787399; DOI=10.1111/j.1600-0854.2006.00429.x;
RA Ni X., Morales C.R.;
RT "The lysosomal trafficking of acid sphingomyelinase is mediated by sortilin
RT and mannose 6-phosphate receptor.";
RL Traffic 7:889-902(2006).
RN [15]
RP POLYMORPHISM.
RX PubMed=18088425; DOI=10.1186/1471-2350-8-79;
RA Dastani Z., Ruel I.L., Engert J.C., Genest J. Jr., Marcil M.;
RT "Sphingomyelin phosphodiesterase-1 (SMPD1) coding variants do not
RT contribute to low levels of high-density lipoprotein cholesterol.";
RL BMC Med. Genet. 8:79-79(2007).
RN [16]
RP FUNCTION, PHOSPHORYLATION AT SER-510, CATALYTIC ACTIVITY, SUBCELLULAR
RP LOCATION, AND MUTAGENESIS OF SER-151; SER-233; SER-250 AND SER-510.
RX PubMed=17303575; DOI=10.1074/jbc.m609424200;
RA Zeidan Y.H., Hannun Y.A.;
RT "Activation of acid sphingomyelinase by protein kinase Cdelta-mediated
RT phosphorylation.";
RL J. Biol. Chem. 282:11549-11561(2007).
RN [17]
RP FUNCTION, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION, GLYCOSYLATION, AND
RP MUTAGENESIS OF SER-510.
RX PubMed=20807762; DOI=10.1074/jbc.m110.125609;
RA Jenkins R.W., Canals D., Idkowiak-Baldys J., Simbari F., Roddy P.,
RA Perry D.M., Kitatani K., Luberto C., Hannun Y.A.;
RT "Regulated secretion of acid sphingomyelinase: implications for selectivity
RT of ceramide formation.";
RL J. Biol. Chem. 285:35706-35718(2010).
RN [18]
RP FUNCTION, CATALYTIC ACTIVITY, AND SUBCELLULAR LOCATION.
RX PubMed=20530211; DOI=10.1083/jcb.201003053;
RA Tam C., Idone V., Devlin C., Fernandes M.C., Flannery A., He X.,
RA Schuchman E., Tabas I., Andrews N.W.;
RT "Exocytosis of acid sphingomyelinase by wounded cells promotes endocytosis
RT and plasma membrane repair.";
RL J. Cell Biol. 189:1027-1038(2010).
RN [19]
RP FUNCTION (MICROBIAL INFECTION), SUBCELLULAR LOCATION, CATALYTIC ACTIVITY,
RP AND ACTIVITY REGULATION.
RX PubMed=22573858; DOI=10.1128/jvi.00136-12;
RA Miller M.E., Adhikary S., Kolokoltsov A.A., Davey R.A.;
RT "Ebolavirus requires acid sphingomyelinase activity and plasma membrane
RT sphingomyelin for infection.";
RL J. Virol. 86:7473-7483(2012).
RN [20]
RP FUNCTION, CATALYTIC ACTIVITY, ACTIVITY REGULATION, AND SUBCELLULAR
RP LOCATION.
RX PubMed=25339683; DOI=10.1194/jlr.m054528;
RA Oninla V.O., Breiden B., Babalola J.O., Sandhoff K.;
RT "Acid sphingomyelinase activity is regulated by membrane lipids and
RT facilitates cholesterol transfer by NPC2.";
RL J. Lipid Res. 55:2606-2619(2014).
RN [21]
RP REVIEW OF FUNCTION AND SUBCELLULAR LOCATION.
RX PubMed=31155842; DOI=10.1111/cmi.13065;
RA Andrews N.W.;
RT "Solving the secretory acid sphingomyelinase puzzle: Insights from
RT lysosome-mediated parasite invasion and plasma membrane repair.";
RL Cell. Microbiol. 21:e13065-e13065(2019).
RN [22]
RP FUNCTION (MICROBIAL INFECTION), ACTIVITY REGULATION, AND CATALYTIC
RP ACTIVITY.
RX PubMed=33163980; DOI=10.1016/j.xcrm.2020.100142;
RA Carpinteiro A., Edwards M.J., Hoffmann M., Kochs G., Gripp B., Weigang S.,
RA Adams C., Carpinteiro E., Gulbins A., Keitsch S., Sehl C., Soddemann M.,
RA Wilker B., Kamler M., Bertsch T., Lang K.S., Patel S., Wilson G.C.,
RA Walter S., Hengel H., Poehlmann S., Lang P.A., Kornhuber J., Becker K.A.,
RA Ahmad S.A., Fassbender K., Gulbins E.;
RT "Pharmacological Inhibition of Acid Sphingomyelinase Prevents Uptake of
RT SARS-CoV-2 by Epithelial Cells.";
RL Cell Rep. 1:100142-100142(2020).
RN [23]
RP X-RAY CRYSTALLOGRAPHY (2.80 ANGSTROMS) OF 47-629 OF MUTANT SER-631 IN
RP COMPLEX WITH ZINC, CATALYTIC ACTIVITY, GLYCOSYLATION AT ASN-88; ASN-177;
RP ASN-337; ASN-397; ASN-505 AND ASN-522, DISULFIDE BONDS, AND SUBUNIT.
RX PubMed=27349982; DOI=10.1016/j.jmb.2016.06.012;
RA Xiong Z.J., Huang J., Poda G., Pomes R., Prive G.G.;
RT "Structure of human acid sphingomyelinase reveals the role of the saposin
RT domain in activating substrate hydrolysis.";
RL J. Mol. Biol. 428:3026-3042(2016).
RN [24]
RP X-RAY CRYSTALLOGRAPHY (2.25 ANGSTROMS) OF 47-629 OF APOENZYME AND IN
RP COMPLEX WITH PHOSPHOCHOLINE AND ZINC, COFACTOR, AND GLYCOSYLATION AT
RP ASN-88; ASN-177; ASN-337; ASN-397; ASN-505 AND ASN-522.
RX PubMed=27725636; DOI=10.1038/ncomms13082;
RA Zhou Y.F., Metcalf M.C., Garman S.C., Edmunds T., Qiu H., Wei R.R.;
RT "Human acid sphingomyelinase structures provide insight to molecular basis
RT of Niemann-Pick disease.";
RL Nat. Commun. 7:13082-13082(2016).
RN [25]
RP VARIANT NPDA SER-579, CHARACTERIZATION OF VARIANT NPDA SER-579, AND
RP CATALYTIC ACTIVITY.
RX PubMed=1718266; DOI=10.1016/0006-291x(91)91697-b;
RA Ferlinz K., Hurwitz R., Sandhoff K.;
RT "Molecular basis of acid sphingomyelinase deficiency in a patient with
RT Niemann-Pick disease type A.";
RL Biochem. Biophys. Res. Commun. 179:1187-1191(1991).
RN [26]
RP VARIANT NPDA LEU-498.
RX PubMed=2023926; DOI=10.1073/pnas.88.9.3748;
RA Levran O., Desnick R.J., Schuchman E.H.;
RT "Niemann-Pick disease: a frequent missense mutation in the acid
RT sphingomyelinase gene of Ashkenazi Jewish type A and B patients.";
RL Proc. Natl. Acad. Sci. U.S.A. 88:3748-3752(1991).
RN [27]
RP VARIANT NPDB ARG-610 DEL.
RX PubMed=1885770; DOI=10.1172/jci115380;
RA Levran O., Desnick R.J., Schuchman E.H.;
RT "Niemann-Pick type B disease. Identification of a single codon deletion in
RT the acid sphingomyelinase gene and genotype/phenotype correlations in type
RT A and B patients.";
RL J. Clin. Invest. 88:806-810(1991).
RN [28]
RP VARIANT NPDA PRO-304.
RX PubMed=1391960;
RA Levran O., Desnick R.J., Schuchman E.H.;
RT "Identification and expression of a common missense mutation (L302P) in the
RT acid sphingomyelinase gene of Ashkenazi Jewish type A Niemann-Pick disease
RT patients.";
RL Blood 80:2081-2087(1992).
RN [29]
RP VARIANT NPDB ARG-438.
RX PubMed=1301192; DOI=10.1002/humu.1380010111;
RA Takahashi T., Desnick R.J., Takada G., Schuchman E.H.;
RT "Identification of a missense mutation (S436R) in the acid sphingomyelinase
RT gene from a Japanese patient with type B Niemann-Pick disease.";
RL Hum. Mutat. 1:70-71(1992).
RN [30]
RP VARIANT NPDA ILE-384, AND VARIANTS NPDB ARG-244 AND SER-385.
RX PubMed=1618760; DOI=10.1016/s0021-9258(18)42312-5;
RA Takahashi T., Suchi M., Desnick R.J., Takada G., Schuchman E.H.;
RT "Identification and expression of five mutations in the human acid
RT sphingomyelinase gene causing types A and B Niemann-Pick disease. Molecular
RT evidence for genetic heterogeneity in the neuronopathic and non-
RT neuronopathic forms.";
RL J. Biol. Chem. 267:12552-12558(1992).
RN [31]
RP VARIANT NPDB GLY-393.
RX PubMed=8051942; DOI=10.1007/bf00735404;
RA Sperl W., Bart G., Vanier M.T., Christomanou H., Baldissera I.,
RA Steichensdorf E., Paschke E.;
RT "A family with visceral course of Niemann-Pick disease, macular halo
RT syndrome and low sphingomyelin degradation rate.";
RL J. Inherit. Metab. Dis. 17:93-103(1994).
RN [32]
RP VARIANT NPDA THR-391.
RX PubMed=8680412; DOI=10.1002/humu.1380060412;
RA Schuchman E.H.;
RT "Two new mutations in the acid sphingomyelinase gene causing type A
RT Niemann-pick disease: N389T and R441X.";
RL Hum. Mutat. 6:352-354(1995).
RN [33]
RP VARIANT NPDA CYS-448.
RX PubMed=8693491; DOI=10.1620/tjem.177.117;
RA Takahashi T., Suchi M., Sato W., Ten S.B., Sakuragawa N., Desnick R.J.,
RA Schuchman E.H., Takada G.;
RT "Identification and expression of a missense mutation (Y446C) in the acid
RT sphingomyelinase gene from a Japanese patient with type A Niemann-Pick
RT disease.";
RL Tohoku J. Exp. Med. 177:117-123(1995).
RN [34]
RP VARIANT NPDB GLN-248.
RX PubMed=8664904;
RX DOI=10.1002/(sici)1098-1004(1996)7:1<65::aid-humu10>3.0.co;2-q;
RA Ida H., Rennert O.M., Maekawa K., Eto Y.;
RT "Identification of three novel mutations in the acid sphingomyelinase gene
RT of Japanese patients with Niemann-Pick disease type A and B.";
RL Hum. Mutat. 7:65-67(1996).
RN [35]
RP VARIANTS NPDA LYS-294 AND PRO-343.
RX PubMed=9266408; DOI=10.1023/a:1005387932546;
RA Pavluu H., Elleder M.;
RT "Two novel mutations in patients with atypical phenotypes of acid
RT sphingomyelinase deficiency.";
RL J. Inherit. Metab. Dis. 20:615-616(1997).
RN [36]
RP CHARACTERIZATION OF VARIANT NPDA LEU-498, FUNCTION, AND COFACTOR.
RX PubMed=9660788; DOI=10.1074/jbc.273.29.18250;
RA Schissel S.L., Keesler G.A., Schuchman E.H., Williams K.J., Tabas I.;
RT "The cellular trafficking and zinc dependence of secretory and lysosomal
RT sphingomyelinase, two products of the acid sphingomyelinase gene.";
RL J. Biol. Chem. 273:18250-18259(1998).
RN [37]
RP VARIANTS NPDB VAL-51; TRP-94; PRO-139; ARG-159; PRO-198; CYS-202; MET-227;
RP CYS-230; ASP-234; SER-247; ARG-250; HIS-291; ALA-325; ARG-332; ASP-359;
RP HIS-378; LEU-378; PRO-381; VAL-415; TYR-423; ARG-433; PRO-434; CYS-437;
RP VAL-454; ASP-458; TRP-476; LEU-477; LEU-482; ASN-490; SER-496; CYS-498;
RP GLN-516; VAL-517; ARG-535; PRO-551; ASN-578; HIS-602 AND PRO-602, AND
RP VARIANT VAL-487.
RX PubMed=12369017; DOI=10.1086/345074;
RA Simonaro C.M., Desnick R.J., McGovern M.M., Wasserstein M.P.,
RA Schuchman E.H.;
RT "The demographics and distribution of type B Niemann-Pick disease: novel
RT mutations lead to new genotype/phenotype correlations.";
RL Am. J. Hum. Genet. 71:1413-1419(2002).
RN [38]
RP VARIANTS NPDA ARG-250; TYR-321; SER-465; LEU-477 AND HIS-539, AND VARIANTS
RP NPDB SER-373 AND ARG-610 DEL.
RX PubMed=12556236; DOI=10.1046/j.1469-1809.2003.00009.x;
RA Sikora J., Pavluu-Pereira H., Elleder M., Roelofs H., Wevers R.A.;
RT "Seven novel Acid sphingomyelinase gene mutations in Niemann-Pick type A
RT and B patients.";
RL Ann. Hum. Genet. 67:63-70(2003).
RN [39]
RP VARIANTS NPDA PRO-105; SER-247; LYS-248; HIS-315; PRO-452; LEU-477;
RP LEU-498; HIS-498 AND CYS-519, AND VARIANT GLN-296.
RX PubMed=15221801; DOI=10.1002/humu.9258;
RA Ricci V., Stroppiano M., Corsolini F., Di Rocco M., Parenti G., Regis S.,
RA Grossi S., Biancheri R., Mazzotti R., Filocamo M.;
RT "Screening of 25 Italian patients with Niemann-Pick A reveals fourteen new
RT mutations, one common and thirteen private, in SMPD1.";
RL Hum. Mutat. 24:105-105(2004).
RN [40]
RP VARIANTS NPDB PRO-105; PRO-227; CYS-246; THR-283; LYS-294 AND ILE-384.
RX PubMed=15241805; DOI=10.1002/humu.9263;
RA Pittis M.G., Ricci V., Guerci V.I., Marcais C., Ciana G., Dardis A.,
RA Gerin F., Stroppiano M., Vanier M.T., Filocamo M., Bembi B.;
RT "Acid sphingomyelinase: identification of nine novel mutations among
RT Italian Niemann Pick type B patients and characterization of in vivo
RT functional in-frame start codon.";
RL Hum. Mutat. 24:186-187(2004).
RN [41]
RP VARIANTS NPDB ALA-132 AND TYR-565, AND CHARACTERIZATION OF VARIANTS NPDB
RP PRO-105; ALA-132; PRO-227; CYS-246; THR-283; TYR-565; HIS-602 AND PRO-602.
RX PubMed=16010684; DOI=10.1002/humu.9353;
RA Dardis A., Zampieri S., Filocamo M., Burlina A., Bembi B., Pittis M.G.;
RT "Functional in vitro characterization of 14 SMPD1 mutations identified in
RT Italian patients affected by Niemann Pick type B disease.";
RL Hum. Mutat. 26:164-164(2005).
RN [42]
RP VARIANTS NPDA ARG-168; LEU-186; HIS-230; VAL-243; ARG-250; GLU-253;
RP ALA-280; HIS-291; LYS-294; PRO-343; HIS-378; TRP-476; ARG-535 AND SER-579,
RP VARIANT ARG-508, CATALYTIC ACTIVITY, AND CHARACTERIZATION OF VARIANTS NPDA
RP LEU-186; GLU-253; ALA-280; LYS-294; PRO-343 AND HIS-378.
RX PubMed=15877209; DOI=10.1007/s10545-005-5671-5;
RA Pavluu-Pereira H., Asfaw B., Poupctova H., Ledvinova J., Sikora J.,
RA Vanier M.T., Sandhoff K., Zeman J., Novotna Z., Chudoba D., Elleder M.;
RT "Acid sphingomyelinase deficiency. Phenotype variability with prevalence of
RT intermediate phenotype in a series of twenty-five Czech and Slovak
RT patients. A multi-approach study.";
RL J. Inherit. Metab. Dis. 28:203-227(2005).
RN [43]
RP VARIANTS NPDB ARG-168 AND ASN-178, AND VARIANT GLY-507.
RX PubMed=16472269; DOI=10.1111/j.1445-5994.2005.01013.x;
RA Muessig K., Harzer K., Mayrhofer H., Kraegeloh-Mann I., Haering H.-U.,
RA Machicao F.;
RT "Clinical findings in Niemann-Pick disease type B.";
RL Intern. Med. J. 36:135-136(2006).
RN [44]
RP CHARACTERIZATION OF VARIANTS NPDA PRO-304 AND LEU-498, CHARACTERIZATION OF
RP VARIANTS NPDB TYR-423 AND ARG-610 DEL, FUNCTION, SUBCELLULAR LOCATION, AND
RP CATALYTIC ACTIVITY.
RX PubMed=18815062; DOI=10.1016/j.ymgme.2008.08.004;
RA Jones I., He X., Katouzian F., Darroch P.I., Schuchman E.H.;
RT "Characterization of common SMPD1 mutations causing types A and B Niemann-
RT Pick disease and generation of mutation-specific mouse models.";
RL Mol. Genet. Metab. 95:152-162(2008).
RN [45]
RP VARIANTS NPDB ARG-332 AND ASP-453.
RX PubMed=19050888; DOI=10.1007/s00277-008-0648-8;
RA Lan M.Y., Lin S.J., Chen Y.F., Peng C.H., Liu Y.F.;
RT "A novel missense mutation of the SMPD1 gene in a Taiwanese patient with
RT type B Niemann-Pick disease.";
RL Ann. Hematol. 88:695-697(2009).
RN [46]
RP VARIANTS NPDA SER-247; CYS-369; PHE-392 DEL; ARG-423; SER-469; GLU-484 AND
RP THR-594 DEL, AND VARIANTS NPDB CYS-230; HIS-378; TRP-476; ALA-488 AND
RP ARG-610 DEL.
RX PubMed=19405096; DOI=10.1002/humu.21018;
RA Rodriguez-Pascau L., Gort L., Schuchman E.H., Vilageliu L., Grinberg D.,
RA Chabas A.;
RT "Identification and characterization of SMPD1 mutations causing Niemann-
RT Pick types A and B in Spanish patients.";
RL Hum. Mutat. 30:1117-1122(2009).
RN [47]
RP VARIANTS NPDA ARG-211 AND HIS-253, VARIANTS NPDB MET-314; ARG-427 AND
RP HIS-525, CHARACTERIZATION OF VARIANTS NPDA ARG-211 AND HIS-253, AND
RP CHARACTERIZATION OF VARIANTS NPDB MET-314; ARG-427 AND HIS-525.
RX PubMed=20386867; DOI=10.2119/molmed.2010.00017;
RA Desnick J.P., Kim J., He X., Wasserstein M.P., Simonaro C.M.,
RA Schuchman E.H.;
RT "Identification and characterization of eight novel SMPD1 mutations causing
RT types A and B Niemann-Pick disease.";
RL Mol. Med. 16:316-321(2010).
RN [48]
RP CATALYTIC ACTIVITY, FUNCTION, SUBCELLULAR LOCATION, AND CHARACTERIZATION OF
RP VARIANTS NPDB HIS-602; PRO-602 AND ARG-610 DEL.
RX PubMed=21098024; DOI=10.1074/jbc.m110.155234;
RA Jenkins R.W., Idkowiak-Baldys J., Simbari F., Canals D., Roddy P.,
RA Riner C.D., Clarke C.J., Hannun Y.A.;
RT "A novel mechanism of lysosomal acid sphingomyelinase maturation:
RT requirement for carboxyl-terminal proteolytic processing.";
RL J. Biol. Chem. 286:3777-3788(2011).
RN [49]
RP VARIANT NPDB PRO-163.
RX PubMed=21621718; DOI=10.1016/s0140-6736(11)60285-7;
RA Meersseman W., Verschueren P., Tousseyn T., De Vos R., Cassiman D.;
RT "PAS-positive macrophages--not always infection.";
RL Lancet 377:1890-1890(2011).
RN [50]
RP VARIANT NPDB SER-522.
RX PubMed=22613662;
RA Hua R., Wu H., Cui Z., Chen J.X., Wang Z.;
RT "A novel SMPD1 mutation in two Chinese sibling patients with type B
RT Niemann-Pick disease.";
RL Chin. Med. J. 125:1511-1512(2012).
RN [51]
RP VARIANTS NPDA ASP-247 AND LEU-572, AND CHARACTERIZATION OF VARIANTS NPDA
RP ASP-247 AND LEU-572.
RX PubMed=23430884; DOI=10.1007/8904_2011_80;
RA Toth B., Erdos M., Szekely A., Ritli L., Bagossi P., Suemegi J., Marodi L.;
RT "Molecular genetic characterization of novel sphingomyelin
RT phosphodiesterase 1 mutations causing niemann-pick disease.";
RL JIMD Rep. 3:125-129(2012).
RN [52]
RP VARIANTS NPDB HIS-91; PRO-105; PRO-163; CYS-230; SER-373; PRO-551 AND
RP ARG-610 DEL, AND VARIANTS NPDA ARG-250; SER-465; LEU-477 AND HIS-539.
RX PubMed=22818240; DOI=10.1016/j.ymgme.2012.06.015;
RA Hollak C.E., de Sonnaville E.S., Cassiman D., Linthorst G.E., Groener J.E.,
RA Morava E., Wevers R.A., Mannens M., Aerts J.M., Meersseman W., Akkerman E.,
RA Niezen-Koning K.E., Mulder M.F., Visser G., Wijburg F.A., Lefeber D.,
RA Poorthuis B.J.;
RT "Acid sphingomyelinase (Asm) deficiency patients in The Netherlands and
RT Belgium: disease spectrum and natural course in attenuated patients.";
RL Mol. Genet. Metab. 107:526-533(2012).
RN [53]
RP VARIANTS NPDA ARG-228 AND ARG-387, AND VARIANTS NPDB CYS-230; SER-247;
RP HIS-378; TRP-476; SER-492; PHE-599 AND ARG-610 DEL.
RX PubMed=23252888; DOI=10.1111/cge.12076;
RA Irun P., Mallen M., Dominguez C., Rodriguez-Sureda V., Alvarez-Sala L.A.,
RA Arslan N., Bermejo N., Guerrero C., Perez de Soto I., Villalon L.,
RA Giraldo P., Pocovi M.;
RT "Identification of seven novel SMPD1 mutations causing Niemann-Pick disease
RT types A and B.";
RL Clin. Genet. 84:356-361(2013).
RN [54]
RP CHARACTERIZATION OF VARIANT NPDB ALA-325, AND CHARACTERIZATION OF VARIANT
RP VAL-487.
RX PubMed=23430512; DOI=10.1007/8904_2012_147;
RA Rhein C., Naumann J., Muehle C., Zill P., Adli M., Hegerl U., Hiemke C.,
RA Mergl R., Moeller H.J., Reichel M., Kornhuber J.;
RT "The acid sphingomyelinase sequence variant p.A487V is not associated with
RT decreased levels of enzymatic activity.";
RL JIMD Rep. 8:1-6(2013).
RN [55]
RP VARIANTS ALA-36; PHE-510 AND GLY-605, VARIANTS NPDA ARG-216; CYS-230;
RP SER-255; ARG-319; PRO-324; ARG-343; ARG-363; HIS-391; ARG-393; SER-426;
RP ILE-494; HIS-498; ARG-535 AND HIS-602, AND VARIANTS NPDB PRO-105; PHE-282;
RP ASP-320; CYS-369; SER-465; LEU-520 AND LYS-549.
RX PubMed=27338287; DOI=10.1002/ajmg.a.37817;
RA Ranganath P., Matta D., Bhavani G.S., Wangnekar S., Jain J.M., Verma I.C.,
RA Kabra M., Puri R.D., Danda S., Gupta N., Girisha K.M., Sankar V.H.,
RA Patil S.J., Ramadevi A.R., Bhat M., Gowrishankar K., Mandal K.,
RA Aggarwal S., Tamhankar P.M., Tilak P., Phadke S.R., Dalal A.;
RT "Spectrum of SMPD1 mutations in Asian-Indian patients with acid
RT sphingomyelinase (ASM)-deficient Niemann-Pick disease.";
RL Am. J. Med. Genet. A 170:2719-2730(2016).
RN [56]
RP VARIANTS NPDB ILE-258; GLN-476; ASP-577; ARG-598 AND CYS-610, VARIANT NPDA
RP PHE-482 DEL, AND REVIEW ON VARIANTS.
RX PubMed=26499107; DOI=10.1002/humu.22923;
RA Zampieri S., Filocamo M., Pianta A., Lualdi S., Gort L., Coll M.J.,
RA Sinnott R., Geberhiwot T., Bembi B., Dardis A.;
RT "SMPD1 mutation update: database and comprehensive analysis of published
RT and novel variants.";
RL Hum. Mutat. 37:139-147(2016).
RN [57]
RP CHARACTERIZATION OF VARIANT NPDB ALA-325, CHARACTERIZATION OF VARIANTS
RP ALA-36; VAL-487 AND ARG-508, AND CATALYTIC ACTIVITY.
RX PubMed=26084044; DOI=10.3390/ijms160613649;
RA Rhein C., Muehle C., Kornhuber J., Reichel M.;
RT "Alleged detrimental mutations in the SMPD1 gene in patients with Niemann-
RT Pick disease.";
RL Int. J. Mol. Sci. 16:13649-13652(2015).
RN [58]
RP FUNCTION, AND CHARACTERIZATION OF VARIANT NPDB ASP-359.
RX PubMed=27659707; DOI=10.1016/j.bbrc.2016.09.096;
RA Acuna M., Castro-Fernandez V., Latorre M., Castro J., Schuchman E.H.,
RA Guixe V., Gonzalez M., Zanlungo S.;
RT "Structural and functional analysis of the ASM p.Ala359Asp mutant that
RT causes acid sphingomyelinase deficiency.";
RL Biochem. Biophys. Res. Commun. 479:496-501(2016).
RN [59]
RP FUNCTION, SUBCELLULAR LOCATION, VARIANT NPDB ASP-359, AND CHARACTERIZATION
RP OF VARIANT NPDB ASP-359.
RX PubMed=25920558; DOI=10.1038/ejhg.2015.89;
RA Acuna M., Martinez P., Moraga C., He X., Moraga M., Hunter B.,
RA Nuernberg P., Gutierrez R.A., Gonzalez M., Schuchman E.H., Santos J.L.,
RA Miquel J.F., Mabe P., Zanlungo S.;
RT "Epidemiological, clinical and biochemical characterization of the
RT p.(Ala359Asp) SMPD1 variant causing Niemann-Pick disease type B.";
RL Eur. J. Hum. Genet. 24:208-213(2016).
CC -!- FUNCTION: Converts sphingomyelin to ceramide (PubMed:1840600,
CC PubMed:18815062, PubMed:27659707, PubMed:25920558, PubMed:25339683,
CC PubMed:33163980, PubMed:12563314). Exists as two enzymatic forms that
CC arise from alternative trafficking of a single protein precursor, one
CC that is targeted to the endolysosomal compartment, whereas the other is
CC released extracellularly (PubMed:21098024, PubMed:9660788,
CC PubMed:20807762). However, in response to various forms of stress,
CC lysosomal exocytosis may represent a major source of the secretory form
CC (PubMed:20530211, PubMed:12563314, PubMed:20807762, PubMed:9393854,
CC PubMed:22573858). {ECO:0000269|PubMed:12563314,
CC ECO:0000269|PubMed:1840600, ECO:0000269|PubMed:18815062,
CC ECO:0000269|PubMed:20530211, ECO:0000269|PubMed:20807762,
CC ECO:0000269|PubMed:21098024, ECO:0000269|PubMed:22573858,
CC ECO:0000269|PubMed:25339683, ECO:0000269|PubMed:25920558,
CC ECO:0000269|PubMed:27659707, ECO:0000269|PubMed:33163980,
CC ECO:0000269|PubMed:9393854, ECO:0000269|PubMed:9660788, ECO:0000305}.
CC -!- FUNCTION: In the lysosomes, converts sphingomyelin to ceramide
CC (PubMed:20807762, PubMed:21098024). Plays an important role in the
CC export of cholesterol from the intraendolysosomal membranes
CC (PubMed:25339683). Also has phospholipase C activities toward 1,2-
CC diacylglycerolphosphocholine and 1,2-diacylglycerolphosphoglycerol
CC (PubMed:25339683). Modulates stress-induced apoptosis through the
CC production of ceramide (PubMed:8706124). {ECO:0000269|PubMed:20807762,
CC ECO:0000269|PubMed:21098024, ECO:0000269|PubMed:25339683,
CC ECO:0000269|PubMed:8706124}.
CC -!- FUNCTION: When secreted, modulates cell signaling with its ability to
CC reorganize the plasma membrane by converting sphingomyelin to ceramide
CC (PubMed:12563314, PubMed:20807762, PubMed:17303575). Secreted form is
CC increased in response to stress and inflammatory mediators such as
CC IL1B, IFNG or TNF as well as upon infection with bacteria and viruses.
CC Produces the release of ceramide in the outer leaflet of the plasma
CC membrane playing a central role in host defense (PubMed:12563314,
CC PubMed:20807762, PubMed:9393854). Ceramide reorganizes these rafts into
CC larger signaling platforms that are required to internalize P.
CC aeruginosa, induce apoptosis and regulate the cytokine response in
CC infected cells (PubMed:12563314). In wounded cells, the lysosomal form
CC is released extracellularly in the presence of Ca(2+) and promotes
CC endocytosis and plasma membrane repair (PubMed:20530211).
CC {ECO:0000269|PubMed:12563314, ECO:0000269|PubMed:17303575,
CC ECO:0000269|PubMed:20530211, ECO:0000269|PubMed:20807762,
CC ECO:0000269|PubMed:9393854}.
CC -!- FUNCTION: (Microbial infection) Secretion is activated by bacteria such
CC as P. aeruginos, N. gonorrhoeae and others, this activation results in
CC the release of ceramide in the outer leaflet of the plasma membrane
CC which facilitates the infection. {ECO:0000269|PubMed:12563314,
CC ECO:0000269|PubMed:9393854, ECO:0000305|PubMed:31155842}.
CC -!- FUNCTION: (Microbial infection) Secretion is activated by human
CC coronaviruses SARS-CoV and SARS-CoV-2 as well as Zaire ebolavirus, this
CC activation results in the release of ceramide in the outer leaflet of
CC the plasma membrane which facilitates the infection.
CC {ECO:0000269|PubMed:22573858, ECO:0000269|PubMed:33163980}.
CC -!- FUNCTION: [Isoform 2]: Lacks residues that bind the cofactor Zn(2+) and
CC has no enzyme activity. {ECO:0000269|PubMed:1840600, ECO:0000305}.
CC -!- FUNCTION: [Isoform 3]: Lacks residues that bind the cofactor Zn(2+) and
CC has no enzyme activity. {ECO:0000269|PubMed:1840600, ECO:0000305}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a sphingomyelin + H2O = an N-acylsphing-4-enine + H(+) +
CC phosphocholine; Xref=Rhea:RHEA:19253, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:17636, ChEBI:CHEBI:52639,
CC ChEBI:CHEBI:295975; EC=3.1.4.12;
CC Evidence={ECO:0000269|PubMed:12563314, ECO:0000269|PubMed:15877209,
CC ECO:0000269|PubMed:1718266, ECO:0000269|PubMed:1840600,
CC ECO:0000269|PubMed:18815062, ECO:0000269|PubMed:22573858,
CC ECO:0000269|PubMed:25339683, ECO:0000269|PubMed:26084044,
CC ECO:0000269|PubMed:27349982, ECO:0000269|PubMed:33163980,
CC ECO:0000269|PubMed:8702487, ECO:0000269|PubMed:8706124};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:19254;
CC Evidence={ECO:0000269|PubMed:25339683, ECO:0000305|PubMed:12563314,
CC ECO:0000305|PubMed:1840600, ECO:0000305|PubMed:22573858,
CC ECO:0000305|PubMed:33163980, ECO:0000305|PubMed:8706124};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + N-(octadecanoyl)-sphing-4-enine-1-phosphocholine = H(+)
CC + N-octadecanoylsphing-4-enine + phosphocholine;
CC Xref=Rhea:RHEA:54284, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:72961, ChEBI:CHEBI:83358, ChEBI:CHEBI:295975;
CC Evidence={ECO:0000269|PubMed:25339683};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:54285;
CC Evidence={ECO:0000269|PubMed:25339683};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=1,2-dihexadecanoyl-sn-glycero-3-phosphocholine + H2O = 1,2-
CC dihexadecanoyl-sn-glycerol + H(+) + phosphocholine;
CC Xref=Rhea:RHEA:45304, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:72999, ChEBI:CHEBI:82929, ChEBI:CHEBI:295975;
CC Evidence={ECO:0000269|PubMed:25339683};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:45305;
CC Evidence={ECO:0000305|PubMed:25339683};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a 1,2-diacyl-sn-glycero-3-phosphocholine + H2O = a 1,2-diacyl-
CC sn-glycerol + H(+) + phosphocholine; Xref=Rhea:RHEA:10604,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:17815,
CC ChEBI:CHEBI:57643, ChEBI:CHEBI:295975; EC=3.1.4.3;
CC Evidence={ECO:0000269|PubMed:25339683};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:10605;
CC Evidence={ECO:0000305|PubMed:25339683};
CC -!- COFACTOR:
CC Name=Zn(2+); Xref=ChEBI:CHEBI:29105;
CC Evidence={ECO:0000269|PubMed:8702487, ECO:0000269|PubMed:9660788};
CC Note=Binds 2 Zn(2+) ions per subunit (PubMed:27349982,
CC PubMed:27725636). {ECO:0000269|PubMed:27349982,
CC ECO:0000269|PubMed:27725636, ECO:0000269|PubMed:8702487,
CC ECO:0000269|PubMed:9660788};
CC -!- ACTIVITY REGULATION: Hydrolysis of liposomal sphingomyelin is
CC stimulated by incorporation of diacylglycerol (DAG), ceramide and free
CC fatty acids into the liposomal membranes (PubMed:25339683).
CC Phosphatidylcholine hydrolysis is inhibited by incorporation of
CC cholesterol, ceramide, DAG, monoacylglycerol and fatty acids
CC (PubMed:25339683). Antidepressants, namely amitriptyline, imipramine,
CC desipramine, fluoxetine, sertraline, escitalopram, and maprotiline
CC inhibit sphingomyelin phosphodiesterase activity (PubMed:33163980,
CC PubMed:22573858). {ECO:0000269|PubMed:22573858,
CC ECO:0000269|PubMed:25339683, ECO:0000269|PubMed:33163980}.
CC -!- ACTIVITY REGULATION: (Microbial infection) The secretory form is
CC activated by P. aeruginosa, this activation results in the release of
CC ceramide in the outer leaflet of the plasma membrane.
CC {ECO:0000269|PubMed:12563314}.
CC -!- ACTIVITY REGULATION: (Microbial infection) The secretory form is
CC activated by human coronavirus SARS-CoV-2, this activation results in
CC the release of ceramide in the outer leaflet of the plasma membrane.
CC {ECO:0000269|PubMed:33163980}.
CC -!- SUBUNIT: Monomer. Interacts with SORT1; the interaction is required for
CC SMPD1 targeting to lysosomes (PubMed:16787399).
CC {ECO:0000269|PubMed:16787399, ECO:0000269|PubMed:27349982}.
CC -!- INTERACTION:
CC P17405; P55210: CASP7; NbExp=6; IntAct=EBI-7095800, EBI-523958;
CC -!- SUBCELLULAR LOCATION: Lysosome {ECO:0000269|PubMed:16787399,
CC ECO:0000269|PubMed:18815062, ECO:0000269|PubMed:20530211,
CC ECO:0000269|PubMed:20807762, ECO:0000269|PubMed:27659707,
CC ECO:0000269|PubMed:9660788}. Lipid droplet
CC {ECO:0000269|PubMed:25339683}. Secreted {ECO:0000269|PubMed:12563314,
CC ECO:0000269|PubMed:16787399, ECO:0000269|PubMed:17303575,
CC ECO:0000269|PubMed:20530211, ECO:0000269|PubMed:20807762,
CC ECO:0000269|PubMed:22573858, ECO:0000269|PubMed:27659707,
CC ECO:0000269|PubMed:8702487, ECO:0000269|PubMed:9030779,
CC ECO:0000269|PubMed:9660788}. Note=The secreted form is induced in a
CC time- and dose-dependent by IL1B and TNF as well as stress and viral
CC infection. This increase of the secreted form seems to be due to
CC exocytosis of the lysosomal form and is Ca(2+)-dependent
CC (PubMed:20807762, PubMed:22573858, PubMed:20530211). Secretion is
CC dependent of phosphorylation at Ser-510 (PubMed:17303575). Secretion is
CC induced by inflammatory mediators such as IL1B, IFNG or TNF as well as
CC infection with bacteria and viruses (PubMed:12563314, PubMed:20807762).
CC {ECO:0000269|PubMed:12563314, ECO:0000269|PubMed:17303575,
CC ECO:0000269|PubMed:20530211, ECO:0000269|PubMed:20807762,
CC ECO:0000269|PubMed:22573858}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=4;
CC Name=1; Synonyms=ASM-1;
CC IsoId=P17405-1; Sequence=Displayed;
CC Name=2; Synonyms=ASM-2;
CC IsoId=P17405-2; Sequence=VSP_000331, VSP_000332;
CC Name=3; Synonyms=ASM-3;
CC IsoId=P17405-3; Sequence=VSP_000333;
CC Name=4;
CC IsoId=P17405-4; Sequence=VSP_046964;
CC -!- PTM: Proteolytically processed (PubMed:21098024, PubMed:9030779).
CC Mature lysosomal form arises from C-terminal proteolytic processing of
CC pro-sphingomyelin phosphodiesterase (PubMed:21098024).
CC {ECO:0000269|PubMed:21098024, ECO:0000269|PubMed:9030779}.
CC -!- PTM: Both lysosomal and secreted forms are glycosylated but they show a
CC differential pattern of glycosylation. {ECO:0000269|PubMed:20807762,
CC ECO:0000269|PubMed:9030779}.
CC -!- PTM: Phosphorylated at Ser-510 by PRKCD upon stress stimuli.
CC Phosphorylation is required for secretion.
CC {ECO:0000269|PubMed:17303575, ECO:0000269|PubMed:20807762,
CC ECO:0000269|PubMed:9030779}.
CC -!- POLYMORPHISM: A common polymorphism arises from a variable number of
CC hexanucleotide repeat sequence within the signal peptide region.
CC {ECO:0000269|PubMed:18088425}.
CC -!- DISEASE: Niemann-Pick disease A (NPDA) [MIM:257200]: An early-onset
CC lysosomal storage disorder caused by failure to hydrolyze sphingomyelin
CC to ceramide. It results in the accumulation of sphingomyelin and other
CC metabolically related lipids in reticuloendothelial and other cell
CC types throughout the body, leading to cell death. Niemann-Pick disease
CC type A is a primarily neurodegenerative disorder characterized by onset
CC within the first year of life, intellectual disability, digestive
CC disorders, failure to thrive, major hepatosplenomegaly, and severe
CC neurologic symptoms. The severe neurological disorders and pulmonary
CC infections lead to an early death, often around the age of four.
CC Clinical features are variable. A phenotypic continuum exists between
CC type A (basic neurovisceral) and type B (purely visceral) forms of
CC Niemann-Pick disease, and the intermediate types encompass a cluster of
CC variants combining clinical features of both types A and B.
CC {ECO:0000269|PubMed:12556236, ECO:0000269|PubMed:1391960,
CC ECO:0000269|PubMed:15221801, ECO:0000269|PubMed:15877209,
CC ECO:0000269|PubMed:1618760, ECO:0000269|PubMed:1718266,
CC ECO:0000269|PubMed:18815062, ECO:0000269|PubMed:19405096,
CC ECO:0000269|PubMed:2023926, ECO:0000269|PubMed:20386867,
CC ECO:0000269|PubMed:22818240, ECO:0000269|PubMed:23252888,
CC ECO:0000269|PubMed:23430884, ECO:0000269|PubMed:26499107,
CC ECO:0000269|PubMed:27338287, ECO:0000269|PubMed:8680412,
CC ECO:0000269|PubMed:8693491, ECO:0000269|PubMed:9266408,
CC ECO:0000269|PubMed:9660788}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Niemann-Pick disease B (NPDB) [MIM:607616]: A late-onset
CC lysosomal storage disorder caused by failure to hydrolyze sphingomyelin
CC to ceramide. It results in the accumulation of sphingomyelin and other
CC metabolically related lipids in reticuloendothelial and other cell
CC types throughout the body, leading to cell death. Clinical signs
CC involve only visceral organs. The most constant sign is
CC hepatosplenomegaly which can be associated with pulmonary symptoms.
CC Patients remain free of neurologic manifestations. However, a
CC phenotypic continuum exists between type A (basic neurovisceral) and
CC type B (purely visceral) forms of Niemann-Pick disease, and the
CC intermediate types encompass a cluster of variants combining clinical
CC features of both types A and B. In Niemann-Pick disease type B, onset
CC of the first symptoms occurs in early childhood and patients can
CC survive into adulthood. {ECO:0000269|PubMed:12369017,
CC ECO:0000269|PubMed:12556236, ECO:0000269|PubMed:1301192,
CC ECO:0000269|PubMed:15241805, ECO:0000269|PubMed:16010684,
CC ECO:0000269|PubMed:1618760, ECO:0000269|PubMed:16472269,
CC ECO:0000269|PubMed:18815062, ECO:0000269|PubMed:1885770,
CC ECO:0000269|PubMed:19050888, ECO:0000269|PubMed:19405096,
CC ECO:0000269|PubMed:20386867, ECO:0000269|PubMed:21098024,
CC ECO:0000269|PubMed:21621718, ECO:0000269|PubMed:22613662,
CC ECO:0000269|PubMed:22818240, ECO:0000269|PubMed:23252888,
CC ECO:0000269|PubMed:23430512, ECO:0000269|PubMed:25920558,
CC ECO:0000269|PubMed:26084044, ECO:0000269|PubMed:26499107,
CC ECO:0000269|PubMed:27338287, ECO:0000269|PubMed:27659707,
CC ECO:0000269|PubMed:8051942, ECO:0000269|PubMed:8664904}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- MISCELLANEOUS: There are two types of sphingomyelinases: ASM (acid),
CC and NSM (neutral).
CC -!- MISCELLANEOUS: [Isoform 1]: Most abundant (90%).
CC -!- MISCELLANEOUS: [Isoform 2]: Intermediate abundance (10%).
CC {ECO:0000305}.
CC -!- MISCELLANEOUS: [Isoform 3]: Low abundance (<1%). {ECO:0000305}.
CC -!- SIMILARITY: Belongs to the acid sphingomyelinase family. {ECO:0000305}.
CC -!- CAUTION: Variants Gln-294 and Val-485 have been originally reported as
CC disease-causing mutations in NPDA and NPDB (PubMed:12369017,
CC PubMed:15221801). These variants have been reclassified as benign
CC polymorphisms (PubMed:23430512). {ECO:0000269|PubMed:12369017,
CC ECO:0000269|PubMed:15221801, ECO:0000269|PubMed:23430512}.
CC -!- WEB RESOURCE: Name=Mendelian genes sphingomyelin phosphodiesterase 1,
CC acid lysosomal (SMPD1); Note=Leiden Open Variation Database (LOVD);
CC URL="https://databases.lovd.nl/shared/genes/SMPD1";
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DR EMBL; M59916; AAA58377.1; -; mRNA.
DR EMBL; M59917; AAA58378.1; -; Genomic_DNA.
DR EMBL; X63600; CAA45145.1; -; Genomic_DNA.
DR EMBL; M81780; AAA75008.1; -; Genomic_DNA.
DR EMBL; M81780; AAA75009.1; -; Genomic_DNA.
DR EMBL; X59960; CAA42584.1; -; mRNA.
DR EMBL; AK292388; BAF85077.1; -; mRNA.
DR EMBL; AC068733; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; X52678; CAA36901.1; -; mRNA.
DR EMBL; X52679; CAA36902.1; -; mRNA.
DR CCDS; CCDS31409.2; -. [P17405-4]
DR CCDS; CCDS44531.1; -. [P17405-1]
DR PIR; S06958; S06958.
DR PIR; S27009; A39825.
DR RefSeq; NP_000534.3; NM_000543.4. [P17405-1]
DR RefSeq; NP_001007594.2; NM_001007593.2. [P17405-4]
DR RefSeq; NP_001305016.1; NM_001318087.1.
DR RefSeq; NP_001305017.1; NM_001318088.1.
DR RefSeq; XP_011518605.1; XM_011520303.1.
DR PDB; 5I81; X-ray; 2.25 A; A=47-631.
DR PDB; 5I85; X-ray; 2.50 A; A=47-631.
DR PDB; 5I8R; X-ray; 3.65 A; A/B/C=47-631.
DR PDB; 5JG8; X-ray; 2.80 A; A/B=47-631.
DR PDBsum; 5I81; -.
DR PDBsum; 5I85; -.
DR PDBsum; 5I8R; -.
DR PDBsum; 5JG8; -.
DR AlphaFoldDB; P17405; -.
DR SMR; P17405; -.
DR BioGRID; 112493; 31.
DR IntAct; P17405; 11.
DR MINT; P17405; -.
DR STRING; 9606.ENSP00000340409; -.
DR BindingDB; P17405; -.
DR ChEMBL; CHEMBL2760; -.
DR DrugBank; DB00381; Amlodipine.
DR DrugBank; DB12151; Brincidofovir.
DR DrugBank; DB00477; Chlorpromazine.
DR DrugBank; DB01151; Desipramine.
DR DrugBank; DB14009; Medical Cannabis.
DR GuidetoPHARMACOLOGY; 2514; -.
DR SwissLipids; SLP:000001748; -.
DR GlyConnect; 2081; 1 N-Linked glycan (1 site).
DR GlyGen; P17405; 8 sites, 2 N-linked glycans (1 site).
DR iPTMnet; P17405; -.
DR PhosphoSitePlus; P17405; -.
DR BioMuta; SMPD1; -.
DR DMDM; 224471897; -.
DR EPD; P17405; -.
DR jPOST; P17405; -.
DR MassIVE; P17405; -.
DR MaxQB; P17405; -.
DR PaxDb; P17405; -.
DR PeptideAtlas; P17405; -.
DR PRIDE; P17405; -.
DR ProteomicsDB; 21562; -.
DR ProteomicsDB; 53470; -. [P17405-1]
DR ProteomicsDB; 53471; -. [P17405-2]
DR ProteomicsDB; 53472; -. [P17405-3]
DR Antibodypedia; 1065; 300 antibodies from 31 providers.
DR DNASU; 6609; -.
DR Ensembl; ENST00000342245.9; ENSP00000340409.4; ENSG00000166311.10. [P17405-1]
DR Ensembl; ENST00000527275.5; ENSP00000435350.1; ENSG00000166311.10. [P17405-4]
DR GeneID; 6609; -.
DR KEGG; hsa:6609; -.
DR MANE-Select; ENST00000342245.9; ENSP00000340409.4; NM_000543.5; NP_000534.3.
DR UCSC; uc001mcw.4; human. [P17405-1]
DR CTD; 6609; -.
DR DisGeNET; 6609; -.
DR GeneCards; SMPD1; -.
DR GeneReviews; SMPD1; -.
DR HGNC; HGNC:11120; SMPD1.
DR HPA; ENSG00000166311; Low tissue specificity.
DR MalaCards; SMPD1; -.
DR MIM; 257200; phenotype.
DR MIM; 607608; gene.
DR MIM; 607616; phenotype.
DR neXtProt; NX_P17405; -.
DR OpenTargets; ENSG00000166311; -.
DR Orphanet; 77293; Chronic visceral acid sphingomyelinase deficiency.
DR Orphanet; 77292; Infantile neurovisceral acid sphingomyelinase deficiency.
DR PharmGKB; PA35969; -.
DR VEuPathDB; HostDB:ENSG00000166311; -.
DR eggNOG; KOG3770; Eukaryota.
DR GeneTree; ENSGT00950000183182; -.
DR InParanoid; P17405; -.
DR OMA; WPTEACA; -.
DR OrthoDB; 1142100at2759; -.
DR PhylomeDB; P17405; -.
DR TreeFam; TF313674; -.
DR BRENDA; 3.1.4.12; 2681.
DR PathwayCommons; P17405; -.
DR Reactome; R-HSA-1660662; Glycosphingolipid metabolism.
DR SignaLink; P17405; -.
DR SIGNOR; P17405; -.
DR BioGRID-ORCS; 6609; 11 hits in 1088 CRISPR screens.
DR ChiTaRS; SMPD1; human.
DR GeneWiki; Sphingomyelin_phosphodiesterase_1; -.
DR GenomeRNAi; 6609; -.
DR Pharos; P17405; Tchem.
DR PRO; PR:P17405; -.
DR Proteomes; UP000005640; Chromosome 11.
DR RNAct; P17405; protein.
DR Bgee; ENSG00000166311; Expressed in type B pancreatic cell and 185 other tissues.
DR ExpressionAtlas; P17405; baseline and differential.
DR Genevisible; P17405; HS.
DR GO; GO:0036019; C:endolysosome; IDA:UniProtKB.
DR GO; GO:0005768; C:endosome; IDA:UniProtKB.
DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB.
DR GO; GO:0005615; C:extracellular space; IDA:UniProtKB.
DR GO; GO:0042599; C:lamellar body; IEA:Ensembl.
DR GO; GO:0005811; C:lipid droplet; IEA:UniProtKB-SubCell.
DR GO; GO:0043202; C:lysosomal lumen; TAS:Reactome.
DR GO; GO:0005764; C:lysosome; IDA:UniProtKB.
DR GO; GO:0005886; C:plasma membrane; IDA:UniProtKB.
DR GO; GO:0061750; F:acid sphingomyelin phosphodiesterase activity; IDA:UniProtKB.
DR GO; GO:0016798; F:hydrolase activity, acting on glycosyl bonds; IEA:UniProtKB-KW.
DR GO; GO:0034480; F:phosphatidylcholine phospholipase C activity; IEA:RHEA.
DR GO; GO:0008081; F:phosphoric diester hydrolase activity; IBA:GO_Central.
DR GO; GO:0004767; F:sphingomyelin phosphodiesterase activity; IDA:UniProtKB.
DR GO; GO:0008270; F:zinc ion binding; IDA:UniProtKB.
DR GO; GO:0071277; P:cellular response to calcium ion; IDA:UniProtKB.
DR GO; GO:0034644; P:cellular response to UV; IDA:UniProtKB.
DR GO; GO:0046513; P:ceramide biosynthetic process; IDA:UniProtKB.
DR GO; GO:0008203; P:cholesterol metabolic process; IEA:Ensembl.
DR GO; GO:0006687; P:glycosphingolipid metabolic process; TAS:Reactome.
DR GO; GO:0043407; P:negative regulation of MAP kinase activity; IMP:BHF-UCL.
DR GO; GO:0007399; P:nervous system development; TAS:ProtInc.
DR GO; GO:0001778; P:plasma membrane repair; IDA:UniProtKB.
DR GO; GO:0043065; P:positive regulation of apoptotic process; IMP:UniProtKB.
DR GO; GO:0045807; P:positive regulation of endocytosis; IDA:UniProtKB.
DR GO; GO:0035307; P:positive regulation of protein dephosphorylation; IMP:BHF-UCL.
DR GO; GO:0042220; P:response to cocaine; IEA:Ensembl.
DR GO; GO:0070555; P:response to interleukin-1; IDA:UniProtKB.
DR GO; GO:0010212; P:response to ionizing radiation; IMP:UniProtKB.
DR GO; GO:0034612; P:response to tumor necrosis factor; IDA:UniProtKB.
DR GO; GO:0034340; P:response to type I interferon; IDA:UniProtKB.
DR GO; GO:0009615; P:response to virus; IDA:UniProtKB.
DR GO; GO:0009410; P:response to xenobiotic stimulus; IEA:Ensembl.
DR GO; GO:0007165; P:signal transduction; TAS:ProtInc.
DR GO; GO:0006685; P:sphingomyelin catabolic process; IDA:UniProtKB.
DR GO; GO:0006684; P:sphingomyelin metabolic process; TAS:ProtInc.
DR GO; GO:0023021; P:termination of signal transduction; IMP:BHF-UCL.
DR GO; GO:0046718; P:viral entry into host cell; IDA:UniProtKB.
DR GO; GO:0042060; P:wound healing; IDA:UniProtKB.
DR CDD; cd00842; MPP_ASMase; 1.
DR DisProt; DP02027; -.
DR Gene3D; 3.60.21.10; -; 1.
DR InterPro; IPR045473; ASM_C.
DR InterPro; IPR041805; ASMase/PPN1_MPP.
DR InterPro; IPR004843; Calcineurin-like_PHP_ApaH.
DR InterPro; IPR029052; Metallo-depent_PP-like.
DR InterPro; IPR011001; Saposin-like.
DR InterPro; IPR008139; SaposinB_dom.
DR InterPro; IPR011160; Sphingomy_PDE.
DR Pfam; PF19272; ASMase_C; 1.
DR Pfam; PF00149; Metallophos; 1.
DR PIRSF; PIRSF000948; Sphingomy_PDE; 1.
DR SMART; SM00741; SapB; 1.
DR SUPFAM; SSF47862; SSF47862; 1.
DR SUPFAM; SSF56300; SSF56300; 1.
DR PROSITE; PS50015; SAP_B; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Direct protein sequencing;
KW Disease variant; Disulfide bond; Glycoprotein; Glycosidase;
KW Host-virus interaction; Hydrolase; Lipid droplet; Lipid metabolism;
KW Lysosome; Metal-binding; Neurodegeneration; Niemann-Pick disease;
KW Phosphoprotein; Reference proteome; Secreted; Signal; Zinc.
FT SIGNAL 1..46
FT CHAIN 47..631
FT /note="Sphingomyelin phosphodiesterase"
FT /id="PRO_0000002323"
FT DOMAIN 87..171
FT /note="Saposin B-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00415"
FT REGION 1..23
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 208
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:27349982,
FT ECO:0007744|PDB:5I81, ECO:0007744|PDB:5I85,
FT ECO:0007744|PDB:5I8R, ECO:0007744|PDB:5JG8"
FT BINDING 210
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:27349982,
FT ECO:0007744|PDB:5I81, ECO:0007744|PDB:5I85,
FT ECO:0007744|PDB:5I8R, ECO:0007744|PDB:5JG8"
FT BINDING 280
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:27349982,
FT ECO:0007744|PDB:5I81, ECO:0007744|PDB:5I85,
FT ECO:0007744|PDB:5I8R, ECO:0007744|PDB:5JG8"
FT BINDING 280
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:27349982,
FT ECO:0007744|PDB:5I81, ECO:0007744|PDB:5I85,
FT ECO:0007744|PDB:5I8R, ECO:0007744|PDB:5JG8"
FT BINDING 320
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:27349982,
FT ECO:0007744|PDB:5I81, ECO:0007744|PDB:5I85,
FT ECO:0007744|PDB:5I8R, ECO:0007744|PDB:5JG8"
FT BINDING 427
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:27349982,
FT ECO:0007744|PDB:5I81, ECO:0007744|PDB:5I85,
FT ECO:0007744|PDB:5I8R, ECO:0007744|PDB:5JG8"
FT BINDING 459
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:27349982,
FT ECO:0007744|PDB:5I81, ECO:0007744|PDB:5I85,
FT ECO:0007744|PDB:5I8R, ECO:0007744|PDB:5JG8"
FT BINDING 461
FT /ligand="Zn(2+)"
FT /ligand_id="ChEBI:CHEBI:29105"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:27349982,
FT ECO:0007744|PDB:5I81, ECO:0007744|PDB:5I85,
FT ECO:0007744|PDB:5I8R, ECO:0007744|PDB:5JG8"
FT MOD_RES 510
FT /note="Phosphoserine; by PKC/PRKCD"
FT /evidence="ECO:0000269|PubMed:17303575"
FT CARBOHYD 88
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00415,
FT ECO:0000269|PubMed:27349982, ECO:0000269|PubMed:9030779,
FT ECO:0007744|PDB:5I81, ECO:0007744|PDB:5I85,
FT ECO:0007744|PDB:5I8R, ECO:0007744|PDB:5JG8"
FT CARBOHYD 177
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00415,
FT ECO:0000269|PubMed:27349982, ECO:0000269|PubMed:9030779,
FT ECO:0007744|PDB:5I81, ECO:0007744|PDB:5I85,
FT ECO:0007744|PDB:5I8R, ECO:0007744|PDB:5JG8"
FT CARBOHYD 337
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00415,
FT ECO:0000269|PubMed:27349982, ECO:0000269|PubMed:9030779,
FT ECO:0007744|PDB:5I81, ECO:0007744|PDB:5I8R,
FT ECO:0007744|PDB:5JG8"
FT CARBOHYD 397
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00415,
FT ECO:0000269|PubMed:27349982, ECO:0000269|PubMed:9030779,
FT ECO:0007744|PDB:5I81, ECO:0007744|PDB:5I85,
FT ECO:0007744|PDB:5I8R, ECO:0007744|PDB:5JG8"
FT CARBOHYD 505
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000269|PubMed:27349982,
FT ECO:0007744|PDB:5I81, ECO:0007744|PDB:5I85,
FT ECO:0007744|PDB:5I8R, ECO:0007744|PDB:5JG8"
FT CARBOHYD 522
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00415,
FT ECO:0000269|PubMed:27349982, ECO:0000269|PubMed:9030779,
FT ECO:0007744|PDB:5I81, ECO:0007744|PDB:5I85,
FT ECO:0007744|PDB:5I8R, ECO:0007744|PDB:5JG8"
FT DISULFID 91..167
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00415,
FT ECO:0000269|PubMed:27349982, ECO:0007744|PDB:5JG8"
FT DISULFID 94..159
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00415,
FT ECO:0000269|PubMed:27349982, ECO:0007744|PDB:5JG8"
FT DISULFID 122..133
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00415,
FT ECO:0000269|PubMed:12631268, ECO:0000269|PubMed:27349982,
FT ECO:0007744|PDB:5JG8"
FT DISULFID 223..228
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00415,
FT ECO:0000269|PubMed:12631268, ECO:0000269|PubMed:27349982,
FT ECO:0007744|PDB:5JG8"
FT DISULFID 229..252
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00415,
FT ECO:0000269|PubMed:12631268, ECO:0000269|PubMed:27349982,
FT ECO:0007744|PDB:5JG8"
FT DISULFID 387..433
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00415,
FT ECO:0000269|PubMed:12631268, ECO:0000269|PubMed:27349982,
FT ECO:0007744|PDB:5JG8"
FT DISULFID 586..590
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00415,
FT ECO:0000269|PubMed:12631268, ECO:0000269|PubMed:27349982,
FT ECO:0007744|PDB:5JG8"
FT DISULFID 596..609
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00415,
FT ECO:0000269|PubMed:12631268, ECO:0000269|PubMed:27349982,
FT ECO:0007744|PDB:5JG8"
FT VAR_SEQ 106
FT /note="Missing (in isoform 4)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_046964"
FT VAR_SEQ 365..420
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000305"
FT /id="VSP_000333"
FT VAR_SEQ 365..376
FT /note="IGGFYALSPYPG -> YLSSVETQEGKR (in isoform 2)"
FT /evidence="ECO:0000305"
FT /id="VSP_000331"
FT VAR_SEQ 377..420
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000305"
FT /id="VSP_000332"
FT VARIANT 36..39
FT /note="Missing (in dbSNP:rs550365194)"
FT /evidence="ECO:0000269|PubMed:1740330,
FT ECO:0000269|PubMed:8407868"
FT /id="VAR_080641"
FT VARIANT 36
FT /note="V -> A (does not affect enzymatic activity;
FT dbSNP:rs1050228)"
FT /evidence="ECO:0000269|PubMed:1740330,
FT ECO:0000269|PubMed:26084044, ECO:0000269|PubMed:27338287"
FT /id="VAR_038191"
FT VARIANT 48..49
FT /note="Missing (in dbSNP:rs3838786)"
FT /evidence="ECO:0000269|PubMed:1292508,
FT ECO:0000269|PubMed:14702039, ECO:0000269|PubMed:1840600,
FT ECO:0000269|PubMed:8407868"
FT /id="VAR_080642"
FT VARIANT 51
FT /note="D -> V (in NPDB; unknown pathological significance;
FT dbSNP:rs748589919)"
FT /evidence="ECO:0000269|PubMed:12369017"
FT /id="VAR_060870"
FT VARIANT 91
FT /note="C -> H (in NPDB; requires 2 nucleotide
FT substitutions)"
FT /evidence="ECO:0000269|PubMed:22818240"
FT /id="VAR_075322"
FT VARIANT 94
FT /note="C -> W (in NPDB)"
FT /evidence="ECO:0000269|PubMed:12369017"
FT /id="VAR_060871"
FT VARIANT 105
FT /note="L -> P (in NPDA and NPDB; expresses protein level
FT comparable to wild-type SMPD1 expressing cells; retains
FT very low enzyme activity; dbSNP:rs751269562)"
FT /evidence="ECO:0000269|PubMed:15221801,
FT ECO:0000269|PubMed:15241805, ECO:0000269|PubMed:16010684,
FT ECO:0000269|PubMed:22818240, ECO:0000269|PubMed:27338287"
FT /id="VAR_060872"
FT VARIANT 132
FT /note="V -> A (in NPDB; expresses protein level comparable
FT to wild-type SMPD1 expressing cells; retains 13% residual
FT enzyme activity)"
FT /evidence="ECO:0000269|PubMed:16010684"
FT /id="VAR_060873"
FT VARIANT 139
FT /note="L -> P (in NPDB; dbSNP:rs797044797)"
FT /evidence="ECO:0000269|PubMed:12369017"
FT /id="VAR_060874"
FT VARIANT 159
FT /note="C -> R (in NPDB; dbSNP:rs727504166)"
FT /evidence="ECO:0000269|PubMed:12369017,
FT ECO:0000269|PubMed:8407868"
FT /id="VAR_011387"
FT VARIANT 163
FT /note="L -> P (in NPDB; dbSNP:rs780134410)"
FT /evidence="ECO:0000269|PubMed:22818240"
FT /id="VAR_075323"
FT VARIANT 168
FT /note="G -> R (in NPDB; also in patients with an
FT intermediate form)"
FT /evidence="ECO:0000269|PubMed:15877209,
FT ECO:0000269|PubMed:16472269"
FT /id="VAR_060875"
FT VARIANT 178
FT /note="I -> N (in NPDB; dbSNP:rs749780769)"
FT /evidence="ECO:0000269|PubMed:16472269"
FT /id="VAR_060876"
FT VARIANT 186
FT /note="P -> L (in NPDA; reduces enzyme activity;
FT intermediate form with clinical features of both Niemann-
FT Pick disease types A and B; dbSNP:rs1057517195)"
FT /evidence="ECO:0000269|PubMed:15877209"
FT /id="VAR_060877"
FT VARIANT 198
FT /note="A -> P (in NPDB; dbSNP:rs797044798)"
FT /evidence="ECO:0000269|PubMed:12369017"
FT /id="VAR_060878"
FT VARIANT 202
FT /note="R -> C (in NPDB; dbSNP:rs749595299)"
FT /evidence="ECO:0000269|PubMed:12369017"
FT /id="VAR_060879"
FT VARIANT 211
FT /note="W -> R (in NPDA; results in less than 0.5% of wild-
FT type activity)"
FT /evidence="ECO:0000269|PubMed:20386867"
FT /id="VAR_068435"
FT VARIANT 216
FT /note="L -> R (in NPDA)"
FT /evidence="ECO:0000269|PubMed:27338287"
FT /id="VAR_077311"
FT VARIANT 227
FT /note="L -> M (in NPDB)"
FT /evidence="ECO:0000269|PubMed:12369017"
FT /id="VAR_060880"
FT VARIANT 227
FT /note="L -> P (in NPDB; expresses protein level comparable
FT to wild-type SMPD1 expressing cells; retains no enzyme
FT activity; dbSNP:rs764317969)"
FT /evidence="ECO:0000269|PubMed:15241805,
FT ECO:0000269|PubMed:16010684"
FT /id="VAR_060881"
FT VARIANT 228
FT /note="C -> R (in NPDA; dbSNP:rs1564923612)"
FT /evidence="ECO:0000269|PubMed:23252888"
FT /id="VAR_075324"
FT VARIANT 230
FT /note="R -> C (in NPDB and NPDA; some patients have a NPDA/
FT NPDB intermediate phenotype; dbSNP:rs989639224 and
FT dbSNP:rs1057516483)"
FT /evidence="ECO:0000269|PubMed:12369017,
FT ECO:0000269|PubMed:19405096, ECO:0000269|PubMed:22818240,
FT ECO:0000269|PubMed:23252888, ECO:0000269|PubMed:27338287"
FT /id="VAR_060882"
FT VARIANT 230
FT /note="R -> H (in NPDA; intermediate form with clinical
FT features of both Niemann-Pick disease types A and B;
FT dbSNP:rs141387770)"
FT /evidence="ECO:0000269|PubMed:15877209"
FT /id="VAR_060883"
FT VARIANT 234
FT /note="G -> D (in NPDB)"
FT /evidence="ECO:0000269|PubMed:12369017"
FT /id="VAR_060884"
FT VARIANT 243
FT /note="A -> V (in NPDA; intermediate form with clinical
FT features of both Niemann-Pick disease types A and B;
FT dbSNP:rs1291958011)"
FT /evidence="ECO:0000269|PubMed:15877209"
FT /id="VAR_060885"
FT VARIANT 244
FT /note="G -> R (in NPDB; dbSNP:rs120074122)"
FT /evidence="ECO:0000269|PubMed:1618760"
FT /id="VAR_005058"
FT VARIANT 246
FT /note="W -> C (in NPDB; expresses protein level comparable
FT to wild-type SMPD1 expressing cells; retains no enzyme
FT activity)"
FT /evidence="ECO:0000269|PubMed:15241805,
FT ECO:0000269|PubMed:16010684"
FT /id="VAR_060886"
FT VARIANT 247
FT /note="G -> D (in NPDA; severe decrease in activity; the
FT mutant is highly unstable; dbSNP:rs1590739350)"
FT /evidence="ECO:0000269|PubMed:23430884"
FT /id="VAR_075325"
FT VARIANT 247
FT /note="G -> S (in NPDA and NPDB; dbSNP:rs587779408)"
FT /evidence="ECO:0000269|PubMed:12369017,
FT ECO:0000269|PubMed:15221801, ECO:0000269|PubMed:19405096,
FT ECO:0000269|PubMed:23252888"
FT /id="VAR_060887"
FT VARIANT 248
FT /note="E -> K (in NPDA; dbSNP:rs200763423)"
FT /evidence="ECO:0000269|PubMed:15221801"
FT /id="VAR_060888"
FT VARIANT 248
FT /note="E -> Q (in NPDB; 30% residual activity;
FT dbSNP:rs200763423)"
FT /evidence="ECO:0000269|PubMed:8664904"
FT /id="VAR_005059"
FT VARIANT 250
FT /note="S -> R (in NPDA and NPDB; also found in patients
FT with an intermediate form; dbSNP:rs750779804)"
FT /evidence="ECO:0000269|PubMed:12369017,
FT ECO:0000269|PubMed:12556236, ECO:0000269|PubMed:15877209,
FT ECO:0000269|PubMed:22818240"
FT /id="VAR_015287"
FT VARIANT 253
FT /note="D -> E (in NPDA; strongly reduces enzyme activity;
FT intermediate form with clinical features of both Niemann-
FT Pick disease types A and B)"
FT /evidence="ECO:0000269|PubMed:15877209"
FT /id="VAR_060889"
FT VARIANT 253
FT /note="D -> H (in NPDA; results in loss of activity;
FT dbSNP:rs398123479)"
FT /evidence="ECO:0000269|PubMed:20386867"
FT /id="VAR_068436"
FT VARIANT 255
FT /note="P -> S (in NPDA)"
FT /evidence="ECO:0000269|PubMed:27338287"
FT /id="VAR_077312"
FT VARIANT 258
FT /note="T -> I (in NPDB)"
FT /evidence="ECO:0000269|PubMed:26499107"
FT /id="VAR_075326"
FT VARIANT 280
FT /note="D -> A (in NPDA; strongly reduces enzyme activity;
FT intermediate form with clinical features of both Niemann-
FT Pick disease types A and B)"
FT /evidence="ECO:0000269|PubMed:15877209"
FT /id="VAR_060890"
FT VARIANT 282
FT /note="P -> F (in NPDB; requires 2 nucleotide
FT substitutions)"
FT /evidence="ECO:0000269|PubMed:27338287"
FT /id="VAR_077313"
FT VARIANT 283
FT /note="A -> T (in NPDB; expresses protein level comparable
FT to wild-type SMPD1 expressing cells; retains no enzyme
FT activity; dbSNP:rs752148586)"
FT /evidence="ECO:0000269|PubMed:15241805,
FT ECO:0000269|PubMed:16010684"
FT /id="VAR_060891"
FT VARIANT 291
FT /note="R -> H (in NPDB; also in patients with an
FT intermediate form; unknown pathological significance;
FT dbSNP:rs1803161)"
FT /evidence="ECO:0000269|PubMed:12369017,
FT ECO:0000269|PubMed:15877209"
FT /id="VAR_060892"
FT VARIANT 294
FT /note="Q -> K (in NPDA; strongly reduces enzyme activity;
FT intermediate form with clinical features of both Niemann-
FT Pick disease types A and B; dbSNP:rs120074128)"
FT /evidence="ECO:0000269|PubMed:15241805,
FT ECO:0000269|PubMed:15877209, ECO:0000269|PubMed:9266408"
FT /id="VAR_060893"
FT VARIANT 296
FT /note="R -> Q (in dbSNP:rs35824453)"
FT /evidence="ECO:0000269|PubMed:15221801"
FT /id="VAR_060894"
FT VARIANT 304
FT /note="L -> P (in NPDA; in 23% of NPDA Ashkenazi Jewish
FT patients; abolishes enzyme activity; dbSNP:rs120074124)"
FT /evidence="ECO:0000269|PubMed:1391960,
FT ECO:0000269|PubMed:18815062"
FT /id="VAR_005060"
FT VARIANT 314
FT /note="V -> M (in NPDB; results in 20% of wild-type
FT activity; dbSNP:rs1228068212)"
FT /evidence="ECO:0000269|PubMed:20386867"
FT /id="VAR_068437"
FT VARIANT 315
FT /note="Y -> H (in NPDA)"
FT /evidence="ECO:0000269|PubMed:15221801"
FT /id="VAR_060895"
FT VARIANT 318
FT /note="V -> E (in dbSNP:rs12575136)"
FT /id="VAR_054642"
FT VARIANT 319
FT /note="G -> R (in NPDA; dbSNP:rs757934797)"
FT /evidence="ECO:0000269|PubMed:27338287"
FT /id="VAR_077314"
FT VARIANT 320
FT /note="N -> D (in NPDB; unknown pathological significance;
FT dbSNP:rs779927660)"
FT /evidence="ECO:0000269|PubMed:27338287"
FT /id="VAR_077315"
FT VARIANT 321
FT /note="H -> Y (in NPDA)"
FT /evidence="ECO:0000269|PubMed:12556236,
FT ECO:0000269|PubMed:22818240"
FT /id="VAR_015288"
FT VARIANT 324
FT /note="T -> I (in dbSNP:rs1050233)"
FT /evidence="ECO:0000269|PubMed:1840600,
FT ECO:0000269|PubMed:2555181, ECO:0000269|PubMed:26084044"
FT /id="VAR_054643"
FT VARIANT 324
FT /note="T -> P (in NPDA; unknown pathological significance)"
FT /evidence="ECO:0000269|PubMed:27338287"
FT /id="VAR_077316"
FT VARIANT 325
FT /note="P -> A (in NPDB; results in 1-4% of wild type
FT activity; dbSNP:rs761308217)"
FT /evidence="ECO:0000269|PubMed:12369017,
FT ECO:0000269|PubMed:23430512, ECO:0000269|PubMed:26084044"
FT /id="VAR_060896"
FT VARIANT 332
FT /note="P -> R (in NPDB; dbSNP:rs202081954)"
FT /evidence="ECO:0000269|PubMed:12369017,
FT ECO:0000269|PubMed:19050888"
FT /id="VAR_060897"
FT VARIANT 343
FT /note="L -> P (in NPDA; strongly reduces enzyme activity;
FT intermediate form with clinical features of both Niemann-
FT Pick disease types A and B)"
FT /evidence="ECO:0000269|PubMed:15877209,
FT ECO:0000269|PubMed:9266408"
FT /id="VAR_060898"
FT VARIANT 343
FT /note="L -> R (in NPDA)"
FT /evidence="ECO:0000269|PubMed:27338287"
FT /id="VAR_077317"
FT VARIANT 359
FT /note="A -> D (in NPDB; sphingomyelinase activity is
FT decreased to 4% of wild-type activity; no effect on protein
FT abundance; no effect on protein localization to lysosome;
FT no effect on protein localization to extracellular space;
FT dbSNP:rs797044800)"
FT /evidence="ECO:0000269|PubMed:12369017,
FT ECO:0000269|PubMed:25920558, ECO:0000269|PubMed:27659707"
FT /id="VAR_060899"
FT VARIANT 363
FT /note="L -> R (in NPDA; unknown pathological significance)"
FT /evidence="ECO:0000269|PubMed:27338287"
FT /id="VAR_077318"
FT VARIANT 369
FT /note="Y -> C (in NPDA; dbSNP:rs372287825)"
FT /evidence="ECO:0000269|PubMed:19405096,
FT ECO:0000269|PubMed:27338287"
FT /id="VAR_060900"
FT VARIANT 373
FT /note="P -> S (in NPDB; dbSNP:rs1342372980)"
FT /evidence="ECO:0000269|PubMed:12556236,
FT ECO:0000269|PubMed:22818240"
FT /id="VAR_015289"
FT VARIANT 378
FT /note="R -> H (in NPDB; reduces enzyme activity; some
FT patients have a NPDA/NPDB intermediate phenotype;
FT dbSNP:rs559088058)"
FT /evidence="ECO:0000269|PubMed:12369017,
FT ECO:0000269|PubMed:15877209, ECO:0000269|PubMed:19405096,
FT ECO:0000269|PubMed:23252888"
FT /id="VAR_060901"
FT VARIANT 378
FT /note="R -> L (in NPDB)"
FT /evidence="ECO:0000269|PubMed:12369017"
FT /id="VAR_060902"
FT VARIANT 381
FT /note="S -> P (in NPDB)"
FT /evidence="ECO:0000269|PubMed:12369017"
FT /id="VAR_060903"
FT VARIANT 384
FT /note="M -> I (in NPDA and NPDB; dbSNP:rs120074121)"
FT /evidence="ECO:0000269|PubMed:15241805,
FT ECO:0000269|PubMed:1618760"
FT /id="VAR_005061"
FT VARIANT 385
FT /note="N -> S (in NPDB; dbSNP:rs120074123)"
FT /evidence="ECO:0000269|PubMed:1618760"
FT /id="VAR_005062"
FT VARIANT 387
FT /note="C -> R (in NPDA)"
FT /evidence="ECO:0000269|PubMed:23252888"
FT /id="VAR_075327"
FT VARIANT 391
FT /note="N -> H (in NPDA)"
FT /evidence="ECO:0000269|PubMed:27338287"
FT /id="VAR_077319"
FT VARIANT 391
FT /note="N -> T (in NPDA)"
FT /evidence="ECO:0000269|PubMed:8680412"
FT /id="VAR_005063"
FT VARIANT 392
FT /note="Missing (in NPDA)"
FT /evidence="ECO:0000269|PubMed:19405096"
FT /id="VAR_060904"
FT VARIANT 393
FT /note="W -> G (in NPDB; low sphingomyelin degradation
FT rates; dbSNP:rs120074125)"
FT /evidence="ECO:0000269|PubMed:8051942"
FT /id="VAR_005064"
FT VARIANT 393
FT /note="W -> R (in NPDA; intermediate form)"
FT /evidence="ECO:0000269|PubMed:27338287"
FT /id="VAR_077320"
FT VARIANT 415
FT /note="A -> V (in NPDB; dbSNP:rs1451199796)"
FT /evidence="ECO:0000269|PubMed:12369017"
FT /id="VAR_060905"
FT VARIANT 423
FT /note="H -> R (in NPDA; dbSNP:rs767492080)"
FT /evidence="ECO:0000269|PubMed:19405096"
FT /id="VAR_060906"
FT VARIANT 423
FT /note="H -> Y (in NPDB; abolishes enzyme activity;
FT dbSNP:rs120074126)"
FT /evidence="ECO:0000269|PubMed:12369017,
FT ECO:0000269|PubMed:18815062"
FT /id="VAR_015290"
FT VARIANT 426
FT /note="G -> S (in NPDA; dbSNP:rs1554935136)"
FT /evidence="ECO:0000269|PubMed:27338287"
FT /id="VAR_077321"
FT VARIANT 427
FT /note="H -> R (in NPDB; results in loss of activity; the
FT patient also carries mutation H-228 that has sufficient
FT activity to account for the Niemann-Pick disease type B
FT phenotype; dbSNP:rs794727629)"
FT /evidence="ECO:0000269|PubMed:20386867"
FT /id="VAR_068438"
FT VARIANT 433
FT /note="C -> R (in NPDB; dbSNP:rs779528546)"
FT /evidence="ECO:0000269|PubMed:12369017"
FT /id="VAR_060907"
FT VARIANT 434
FT /note="L -> P (in NPDB)"
FT /evidence="ECO:0000269|PubMed:12369017"
FT /id="VAR_060908"
FT VARIANT 437
FT /note="W -> C (in NPDB)"
FT /evidence="ECO:0000269|PubMed:12369017"
FT /id="VAR_060909"
FT VARIANT 438
FT /note="S -> R (in NPDB; dbSNP:rs267607073)"
FT /evidence="ECO:0000269|PubMed:1301192"
FT /id="VAR_005065"
FT VARIANT 448
FT /note="Y -> C (in NPDA; dbSNP:rs747143343)"
FT /evidence="ECO:0000269|PubMed:8693491"
FT /id="VAR_011388"
FT VARIANT 452
FT /note="L -> P (in NPDA)"
FT /evidence="ECO:0000269|PubMed:15221801"
FT /id="VAR_060910"
FT VARIANT 453
FT /note="A -> D (in NPDB)"
FT /evidence="ECO:0000269|PubMed:19050888"
FT /id="VAR_068439"
FT VARIANT 454
FT /note="A -> V (in NPDB; dbSNP:rs1402734026)"
FT /evidence="ECO:0000269|PubMed:12369017"
FT /id="VAR_060911"
FT VARIANT 458
FT /note="G -> D (in NPDB)"
FT /evidence="ECO:0000269|PubMed:12369017"
FT /id="VAR_060912"
FT VARIANT 465
FT /note="F -> S (in NPDA; dbSNP:rs1319643225)"
FT /evidence="ECO:0000269|PubMed:12556236,
FT ECO:0000269|PubMed:27338287"
FT /id="VAR_015291"
FT VARIANT 469
FT /note="Y -> S (in NPDA; dbSNP:rs267607074)"
FT /evidence="ECO:0000269|PubMed:19405096"
FT /id="VAR_060913"
FT VARIANT 476
FT /note="R -> Q (in NPDB; unknown pathological significance;
FT dbSNP:rs763566905)"
FT /evidence="ECO:0000269|PubMed:26499107"
FT /id="VAR_075328"
FT VARIANT 476
FT /note="R -> W (in NPDB; some patients have a NPDA/NPDB
FT intermediate phenotype; dbSNP:rs182812968)"
FT /evidence="ECO:0000269|PubMed:12369017,
FT ECO:0000269|PubMed:15877209, ECO:0000269|PubMed:19405096,
FT ECO:0000269|PubMed:23252888"
FT /id="VAR_060914"
FT VARIANT 477
FT /note="P -> L (in NPDA and NPDB; dbSNP:rs753508874)"
FT /evidence="ECO:0000269|PubMed:12369017,
FT ECO:0000269|PubMed:12556236, ECO:0000269|PubMed:15221801,
FT ECO:0000269|PubMed:22818240"
FT /id="VAR_015292"
FT VARIANT 482
FT /note="F -> L (in NPDB)"
FT /evidence="ECO:0000269|PubMed:12369017"
FT /id="VAR_060915"
FT VARIANT 482
FT /note="Missing (in NPDA; unknown pathological
FT significance)"
FT /evidence="ECO:0000269|PubMed:26499107"
FT /id="VAR_075329"
FT VARIANT 484
FT /note="A -> E (in NPDA; dbSNP:rs267607075)"
FT /evidence="ECO:0000269|PubMed:19405096"
FT /id="VAR_060916"
FT VARIANT 487
FT /note="A -> V (does not affect enzymatic activity;
FT dbSNP:rs141641266)"
FT /evidence="ECO:0000269|PubMed:12369017,
FT ECO:0000269|PubMed:23430512, ECO:0000269|PubMed:26084044"
FT /id="VAR_060917"
FT VARIANT 488
FT /note="T -> A (in NPDB)"
FT /evidence="ECO:0000269|PubMed:19405096"
FT /id="VAR_060918"
FT VARIANT 490
FT /note="Y -> N (in NPDB; dbSNP:rs398123477)"
FT /evidence="ECO:0000269|PubMed:12369017"
FT /id="VAR_060919"
FT VARIANT 492
FT /note="G -> S (in NPDB; dbSNP:rs144873307)"
FT /evidence="ECO:0000269|PubMed:23252888"
FT /id="VAR_075330"
FT VARIANT 494
FT /note="N -> I (in NPDA; intermediate form)"
FT /evidence="ECO:0000269|PubMed:27338287"
FT /id="VAR_077322"
FT VARIANT 496
FT /note="G -> S (in NPDB; dbSNP:rs1554935371)"
FT /evidence="ECO:0000269|PubMed:12369017"
FT /id="VAR_060920"
FT VARIANT 498
FT /note="R -> C (in NPDB; dbSNP:rs769904764)"
FT /evidence="ECO:0000269|PubMed:12369017"
FT /id="VAR_060921"
FT VARIANT 498
FT /note="R -> H (in NPDA; dbSNP:rs120074117)"
FT /evidence="ECO:0000269|PubMed:15221801,
FT ECO:0000269|PubMed:27338287"
FT /id="VAR_060922"
FT VARIANT 498
FT /note="R -> L (in NPDA; in 32% of NPDA Ashkenazi Jewish
FT patients; nearly abolishes enzyme activity;
FT dbSNP:rs120074117)"
FT /evidence="ECO:0000269|PubMed:15221801,
FT ECO:0000269|PubMed:18815062, ECO:0000269|PubMed:2023926,
FT ECO:0000269|PubMed:9660788"
FT /id="VAR_005066"
FT VARIANT 507
FT /note="S -> G"
FT /evidence="ECO:0000269|PubMed:16472269"
FT /id="VAR_060923"
FT VARIANT 508
FT /note="G -> R (does not affect enzymatic activity;
FT dbSNP:rs1050239)"
FT /evidence="ECO:0000269|PubMed:1292508,
FT ECO:0000269|PubMed:14702039, ECO:0000269|PubMed:15877209,
FT ECO:0000269|PubMed:1840600, ECO:0000269|PubMed:2555181"
FT /id="VAR_054644"
FT VARIANT 510
FT /note="S -> F (in dbSNP:rs200652683)"
FT /evidence="ECO:0000269|PubMed:27338287"
FT /id="VAR_077323"
FT VARIANT 516
FT /note="H -> Q (in NPDB)"
FT /evidence="ECO:0000269|PubMed:12369017"
FT /id="VAR_060924"
FT VARIANT 517
FT /note="E -> V (in NPDB; dbSNP:rs142787001)"
FT /evidence="ECO:0000269|PubMed:12369017"
FT /id="VAR_060925"
FT VARIANT 519
FT /note="Y -> C (in NPDA; dbSNP:rs371837210)"
FT /evidence="ECO:0000269|PubMed:15221801"
FT /id="VAR_060926"
FT VARIANT 520
FT /note="I -> L (in NPDB)"
FT /evidence="ECO:0000269|PubMed:27338287"
FT /id="VAR_077324"
FT VARIANT 522
FT /note="N -> S (in NPDB)"
FT /evidence="ECO:0000269|PubMed:22613662"
FT /id="VAR_068440"
FT VARIANT 525
FT /note="Q -> H (in NPDB; results in 64% of wild-type
FT activity)"
FT /evidence="ECO:0000269|PubMed:20386867"
FT /id="VAR_068441"
FT VARIANT 535
FT /note="W -> R (in NPDB and NPDA; also in patients with an
FT intermediate form; dbSNP:rs1554935555)"
FT /evidence="ECO:0000269|PubMed:12369017,
FT ECO:0000269|PubMed:15877209, ECO:0000269|PubMed:27338287"
FT /id="VAR_060927"
FT VARIANT 539
FT /note="Y -> H (in NPDA)"
FT /evidence="ECO:0000269|PubMed:12556236,
FT ECO:0000269|PubMed:22818240"
FT /id="VAR_015293"
FT VARIANT 549
FT /note="N -> K (in NPDB)"
FT /evidence="ECO:0000269|PubMed:27338287"
FT /id="VAR_077325"
FT VARIANT 551
FT /note="L -> P (in NPDB)"
FT /evidence="ECO:0000269|PubMed:12369017,
FT ECO:0000269|PubMed:22818240"
FT /id="VAR_060928"
FT VARIANT 565
FT /note="D -> Y (in NPDB; expresses protein level comparable
FT to wild-type SMPD1 expressing cells; retains 6.8% residual
FT enzyme activity)"
FT /evidence="ECO:0000269|PubMed:16010684"
FT /id="VAR_060929"
FT VARIANT 572
FT /note="F -> L (in NPDA; results in decreased activity;
FT decreased stability)"
FT /evidence="ECO:0000269|PubMed:23430884"
FT /id="VAR_075331"
FT VARIANT 577
FT /note="H -> D (in NPDB; unknown pathological significance)"
FT /evidence="ECO:0000269|PubMed:26499107"
FT /id="VAR_075332"
FT VARIANT 578
FT /note="K -> N (in NPDB; dbSNP:rs747342458)"
FT /evidence="ECO:0000269|PubMed:12369017"
FT /id="VAR_060930"
FT VARIANT 579
FT /note="G -> S (in NPDA; impairs enzyme activity; also in
FT patients with an intermediate form; dbSNP:rs120074119)"
FT /evidence="ECO:0000269|PubMed:15877209,
FT ECO:0000269|PubMed:1718266"
FT /id="VAR_005067"
FT VARIANT 594
FT /note="Missing (in NPDA)"
FT /evidence="ECO:0000269|PubMed:19405096"
FT /id="VAR_060931"
FT VARIANT 598
FT /note="Q -> R (in NPDB; dbSNP:rs1554935731)"
FT /evidence="ECO:0000269|PubMed:26499107"
FT /id="VAR_075333"
FT VARIANT 599
FT /note="L -> F (in NPDB; unknown pathological significance;
FT dbSNP:rs138531908)"
FT /evidence="ECO:0000269|PubMed:23252888"
FT /id="VAR_075334"
FT VARIANT 602
FT /note="R -> H (in NPDB and NPDA; expresses protein level
FT comparable to wild-type SMPD1 expressing cells; retains
FT about 10% residual enzyme activity; loss of location to
FT lysosome; dbSNP:rs370129081)"
FT /evidence="ECO:0000269|PubMed:12369017,
FT ECO:0000269|PubMed:16010684, ECO:0000269|PubMed:21098024,
FT ECO:0000269|PubMed:27338287"
FT /id="VAR_060932"
FT VARIANT 602
FT /note="R -> P (in NPDB; expresses protein level comparable
FT to wild-type SMPD1 expressing cells; retains very low
FT enzyme activity; loss of location to lysosome)"
FT /evidence="ECO:0000269|PubMed:12369017,
FT ECO:0000269|PubMed:16010684, ECO:0000269|PubMed:21098024"
FT /id="VAR_060933"
FT VARIANT 605
FT /note="S -> G"
FT /evidence="ECO:0000269|PubMed:27338287"
FT /id="VAR_077326"
FT VARIANT 610
FT /note="R -> C (in NPDB; unknown pathological significance;
FT dbSNP:rs375915127)"
FT /evidence="ECO:0000269|PubMed:26499107"
FT /id="VAR_075335"
FT VARIANT 610
FT /note="Missing (in NPDB; nearly abolishes enzyme activity;
FT some patients have a NPDA/NPDB intermediate phenotype; loss
FT of location to lysosome)"
FT /evidence="ECO:0000269|PubMed:12556236,
FT ECO:0000269|PubMed:18815062, ECO:0000269|PubMed:1885770,
FT ECO:0000269|PubMed:19405096, ECO:0000269|PubMed:21098024,
FT ECO:0000269|PubMed:22818240, ECO:0000269|PubMed:23252888"
FT /id="VAR_005068"
FT MUTAGEN 88
FT /note="N->G: No effect on sphingomyelin phosphodiesterase
FT activity. No effect on secretion."
FT /evidence="ECO:0000269|PubMed:9030779"
FT MUTAGEN 151
FT /note="S->A: No effect on sphingomyelin phosphodiesterase
FT activity. No effect on subcellular location. No effect on
FT phosphorylation by PRKCD."
FT /evidence="ECO:0000269|PubMed:17303575"
FT MUTAGEN 177
FT /note="N->G: Reduces protein levels. Reduces sphingomyelin
FT phosphodiesterase activity. No effect on secretion."
FT /evidence="ECO:0000269|PubMed:9030779"
FT MUTAGEN 233
FT /note="S->A: No effect on sphingomyelin phosphodiesterase
FT activity. No effect on endolysosome location. No effect on
FT phosphorylation by PRKCD."
FT /evidence="ECO:0000269|PubMed:17303575"
FT MUTAGEN 250
FT /note="S->A: No effect on sphingomyelin phosphodiesterase
FT activity. No effect on endolysosome location. No effect on
FT phosphorylation by PRKCD."
FT /evidence="ECO:0000269|PubMed:17303575"
FT MUTAGEN 337
FT /note="N->G: No effect on sphingomyelin phosphodiesterase
FT activity. No effect on secretion."
FT /evidence="ECO:0000269|PubMed:9030779"
FT MUTAGEN 397
FT /note="N->G: Reduces sphingomyelin phosphodiesterase
FT activity. No effect on secretion."
FT /evidence="ECO:0000269|PubMed:9030779"
FT MUTAGEN 505
FT /note="N->G: Loss of sphingomyelin phosphodiesterase
FT activity. Loss of secretion."
FT /evidence="ECO:0000269|PubMed:9030779"
FT MUTAGEN 510
FT /note="S->A: Abolishes constitutive secretion and decreases
FT secretion in response to IL1B. No effect on lysosomal
FT targeting. No effect on sphingomyelin phosphodiesterase
FT activity. No effect on endolysosome location. Abolishes
FT phosphorylation by PRKCD."
FT /evidence="ECO:0000269|PubMed:17303575,
FT ECO:0000269|PubMed:20807762"
FT MUTAGEN 522
FT /note="N->G: Loss of sphingomyelin phosphodiesterase
FT activity. Loss of secretion."
FT /evidence="ECO:0000269|PubMed:9030779"
FT CONFLICT 270
FT /note="G -> D (in Ref. 5; BAF85077)"
FT /evidence="ECO:0000305"
FT HELIX 87..89
FT /evidence="ECO:0007829|PDB:5I81"
FT HELIX 90..105
FT /evidence="ECO:0007829|PDB:5I81"
FT HELIX 108..124
FT /evidence="ECO:0007829|PDB:5I81"
FT HELIX 130..150
FT /evidence="ECO:0007829|PDB:5I81"
FT TURN 151..153
FT /evidence="ECO:0007829|PDB:5I81"
FT HELIX 155..163
FT /evidence="ECO:0007829|PDB:5I81"
FT TURN 165..167
FT /evidence="ECO:0007829|PDB:5I81"
FT STRAND 200..206
FT /evidence="ECO:0007829|PDB:5I81"
FT STRAND 224..227
FT /evidence="ECO:0007829|PDB:5I81"
FT STRAND 249..251
FT /evidence="ECO:0007829|PDB:5I81"
FT HELIX 256..264
FT /evidence="ECO:0007829|PDB:5I81"
FT HELIX 267..269
FT /evidence="ECO:0007829|PDB:5I81"
FT STRAND 273..277
FT /evidence="ECO:0007829|PDB:5I81"
FT HELIX 291..309
FT /evidence="ECO:0007829|PDB:5I81"
FT STRAND 314..316
FT /evidence="ECO:0007829|PDB:5I81"
FT STRAND 322..325
FT /evidence="ECO:0007829|PDB:5I81"
FT STRAND 336..340
FT /evidence="ECO:0007829|PDB:5JG8"
FT HELIX 341..350
FT /evidence="ECO:0007829|PDB:5I81"
FT TURN 352..354
FT /evidence="ECO:0007829|PDB:5I81"
FT HELIX 357..366
FT /evidence="ECO:0007829|PDB:5I81"
FT STRAND 369..374
FT /evidence="ECO:0007829|PDB:5I81"
FT STRAND 377..381
FT /evidence="ECO:0007829|PDB:5I81"
FT HELIX 384..387
FT /evidence="ECO:0007829|PDB:5I81"
FT HELIX 392..395
FT /evidence="ECO:0007829|PDB:5I81"
FT HELIX 401..403
FT /evidence="ECO:0007829|PDB:5I81"
FT HELIX 404..418
FT /evidence="ECO:0007829|PDB:5I81"
FT STRAND 421..425
FT /evidence="ECO:0007829|PDB:5I81"
FT HELIX 430..432
FT /evidence="ECO:0007829|PDB:5I81"
FT HELIX 435..447
FT /evidence="ECO:0007829|PDB:5I81"
FT TURN 448..451
FT /evidence="ECO:0007829|PDB:5I81"
FT STRAND 452..457
FT /evidence="ECO:0007829|PDB:5I81"
FT STRAND 464..469
FT /evidence="ECO:0007829|PDB:5I81"
FT TURN 471..473
FT /evidence="ECO:0007829|PDB:5I81"
FT STRAND 476..483
FT /evidence="ECO:0007829|PDB:5I81"
FT TURN 490..492
FT /evidence="ECO:0007829|PDB:5I81"
FT STRAND 496..503
FT /evidence="ECO:0007829|PDB:5I81"
FT STRAND 513..520
FT /evidence="ECO:0007829|PDB:5I81"
FT HELIX 523..526
FT /evidence="ECO:0007829|PDB:5I81"
FT STRAND 536..540
FT /evidence="ECO:0007829|PDB:5I81"
FT HELIX 541..545
FT /evidence="ECO:0007829|PDB:5I81"
FT HELIX 552..563
FT /evidence="ECO:0007829|PDB:5I81"
FT HELIX 566..576
FT /evidence="ECO:0007829|PDB:5I81"
FT TURN 577..579
FT /evidence="ECO:0007829|PDB:5I81"
FT HELIX 588..599
FT /evidence="ECO:0007829|PDB:5I81"
FT STRAND 602..604
FT /evidence="ECO:0007829|PDB:5JG8"
FT HELIX 606..609
FT /evidence="ECO:0007829|PDB:5I81"
FT TURN 610..612
FT /evidence="ECO:0007829|PDB:5I81"
SQ SEQUENCE 631 AA; 69936 MW; F229709F6A9B0E9E CRC64;
MPRYGASLRQ SCPRSGREQG QDGTAGAPGL LWMGLVLALA LALALALALS DSRVLWAPAE
AHPLSPQGHP ARLHRIVPRL RDVFGWGNLT CPICKGLFTA INLGLKKEPN VARVGSVAIK
LCNLLKIAPP AVCQSIVHLF EDDMVEVWRR SVLSPSEACG LLLGSTCGHW DIFSSWNISL
PTVPKPPPKP PSPPAPGAPV SRILFLTDLH WDHDYLEGTD PDCADPLCCR RGSGLPPASR
PGAGYWGEYS KCDLPLRTLE SLLSGLGPAG PFDMVYWTGD IPAHDVWHQT RQDQLRALTT
VTALVRKFLG PVPVYPAVGN HESTPVNSFP PPFIEGNHSS RWLYEAMAKA WEPWLPAEAL
RTLRIGGFYA LSPYPGLRLI SLNMNFCSRE NFWLLINSTD PAGQLQWLVG ELQAAEDRGD
KVHIIGHIPP GHCLKSWSWN YYRIVARYEN TLAAQFFGHT HVDEFEVFYD EETLSRPLAV
AFLAPSATTY IGLNPGYRVY QIDGNYSGSS HVVLDHETYI LNLTQANIPG AIPHWQLLYR
ARETYGLPNT LPTAWHNLVY RMRGDMQLFQ TFWFLYHKGH PPSEPCGTPC RLATLCAQLS
ARADSPALCR HLMPDGSLPE AQSLWPRPLF C
