NPHP4_HUMAN
ID NPHP4_HUMAN Reviewed; 1426 AA.
AC O75161; Q8IWC0;
DT 27-JAN-2003, integrated into UniProtKB/Swiss-Prot.
DT 27-JAN-2003, sequence version 2.
DT 03-AUG-2022, entry version 171.
DE RecName: Full=Nephrocystin-4;
DE AltName: Full=Nephroretinin;
GN Name=NPHP4; Synonyms=KIAA0673;
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] (ISOFORM 1), INTERACTION WITH NPHP1, TISSUE
RP SPECIFICITY, INVOLVEMENT IN SLSN4, AND VARIANT NPHP4 SER-991.
RX PubMed=12244321; DOI=10.1038/ng996;
RA Mollet G., Salomon R., Gribouval O., Silbermann F., Bacq D., Landthaler G.,
RA Milford D., Nayir A., Rizzoni G., Antignac C., Saunier S.;
RT "The gene mutated in juvenile nephronophthisis type 4 encodes a novel
RT protein that interacts with nephrocystin.";
RL Nat. Genet. 32:300-305(2002).
RN [2]
RP ERRATUM OF PUBMED:12244321.
RA Mollet G., Salomon R., Gribouval O., Silbermann F., Bacq D., Landthaler G.,
RA Milford D., Nayir A., Rizzoni G., Antignac C., Saunier S.;
RL Nat. Genet. 32:459-459(2002).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANT NPHP4 ARG-754, AND VARIANT
RP TRP-848.
RC TISSUE=Kidney;
RX PubMed=12205563; DOI=10.1086/344395;
RA Otto E., Hoefele J., Ruf R., Mueller A.M., Hiller K.S., Wolf M.T.F.,
RA Schuermann M.J., Becker A., Birkenhaeger R., Sudbrack R., Hennies H.C.,
RA Nuernberg P., Hildebrandt F.;
RT "A gene mutated in nephronophthisis and retinitis pigmentosa encodes a
RT novel protein, nephroretinin, conserved in evolution.";
RL Am. J. Hum. Genet. 71:1161-1167(2002).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=16710414; DOI=10.1038/nature04727;
RA Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A.,
RA Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C.,
RA Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K.,
RA Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C.,
RA Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W.,
RA Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J.,
RA Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J.,
RA Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y.,
RA Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J.,
RA Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H.,
RA Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L.,
RA Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J.,
RA Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S.,
RA Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K.,
RA Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R.,
RA Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M.,
RA Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S.,
RA Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J.,
RA Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W.,
RA McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N.,
RA Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V.,
RA Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J.,
RA Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E.,
RA Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S.,
RA Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M.,
RA White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H.,
RA Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E.,
RA Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G.,
RA Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R.;
RT "The DNA sequence and biological annotation of human chromosome 1.";
RL Nature 441:315-321(2006).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton 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 [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Testis;
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 [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 212-1426 (ISOFORM 1).
RC TISSUE=Brain;
RX PubMed=9734811; DOI=10.1093/dnares/5.3.169;
RA Ishikawa K., Nagase T., Suyama M., Miyajima N., Tanaka A., Kotani H.,
RA Nomura N., Ohara O.;
RT "Prediction of the coding sequences of unidentified human genes. X. The
RT complete sequences of 100 new cDNA clones from brain which can code for
RT large proteins in vitro.";
RL DNA Res. 5:169-176(1998).
RN [8]
RP INTERACTION WITH NPHP1.
RX PubMed=15661758; DOI=10.1093/hmg/ddi061;
RA Mollet G., Silbermann F., Delous M., Salomon R., Antignac C., Saunier S.;
RT "Characterization of the nephrocystin/nephrocystin-4 complex and
RT subcellular localization of nephrocystin-4 to primary cilia and
RT centrosomes.";
RL Hum. Mol. Genet. 14:645-656(2005).
RN [9]
RP INTERACTION WITH RPGRIP1, INVOLVEMENT IN NPHP4, CHARACTERIZATION OF VARIANT
RP NPHP4 ARG-754, AND CHARACTERIZATION OF VARIANTS HIS-740 AND TRP-848.
RX PubMed=16339905; DOI=10.1073/pnas.0505774102;
RA Roepman R., Letteboer S.J., Arts H.H., van Beersum S.E., Lu X., Krieger E.,
RA Ferreira P.A., Cremers F.P.;
RT "Interaction of nephrocystin-4 and RPGRIP1 is disrupted by nephronophthisis
RT or Leber congenital amaurosis-associated mutations.";
RL Proc. Natl. Acad. Sci. U.S.A. 102:18520-18525(2005).
RN [10]
RP INTERACTION WITH RPGRIP1L, SUBCELLULAR LOCATION, INVOLVEMENT IN NPHP4,
RP CHARACTERIZATION OF VARIANT NPHP4 ARG-754, AND CHARACTERIZATION OF VARIANTS
RP HIS-740 AND TRP-848.
RX PubMed=17558407; DOI=10.1038/ng2069;
RA Arts H.H., Doherty D., van Beersum S.E.C., Parisi M.A., Letteboer S.J.F.,
RA Gorden N.T., Peters T.A., Maerker T., Voesenek K., Kartono A., Ozyurek H.,
RA Farin F.M., Kroes H.Y., Wolfrum U., Brunner H.G., Cremers F.P.M.,
RA Glass I.A., Knoers N.V.A.M., Roepman R.;
RT "Mutations in the gene encoding the basal body protein RPGRIP1L, a
RT nephrocystin-4 interactor, cause Joubert syndrome.";
RL Nat. Genet. 39:882-888(2007).
RN [11]
RP FUNCTION, AND INTERACTION WITH PALS1; INADL AND PARD6A.
RX PubMed=19755384; DOI=10.1093/hmg/ddp434;
RA Delous M., Hellman N.E., Gaude H.M., Silbermann F., Le Bivic A.,
RA Salomon R., Antignac C., Saunier S.;
RT "Nephrocystin-1 and nephrocystin-4 are required for epithelial
RT morphogenesis and associate with PALS1/PATJ and Par6.";
RL Hum. Mol. Genet. 18:4711-4723(2009).
RN [12]
RP FUNCTION.
RX PubMed=21565611; DOI=10.1016/j.cell.2011.04.019;
RA Sang L., Miller J.J., Corbit K.C., Giles R.H., Brauer M.J., Otto E.A.,
RA Baye L.M., Wen X., Scales S.J., Kwong M., Huntzicker E.G., Sfakianos M.K.,
RA Sandoval W., Bazan J.F., Kulkarni P., Garcia-Gonzalo F.R., Seol A.D.,
RA O'Toole J.F., Held S., Reutter H.M., Lane W.S., Rafiq M.A., Noor A.,
RA Ansar M., Devi A.R., Sheffield V.C., Slusarski D.C., Vincent J.B.,
RA Doherty D.A., Hildebrandt F., Reiter J.F., Jackson P.K.;
RT "Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy disease genes
RT and pathways.";
RL Cell 145:513-528(2011).
RN [13]
RP INTERACTION WITH RPGRIP1.
RX PubMed=21224891; DOI=10.1038/ejhg.2010.217;
RA Fernandez-Martinez L., Letteboer S., Mardin C.Y., Weisschuh N., Gramer E.,
RA Weber B.H., Rautenstrauss B., Ferreira P.A., Kruse F.E., Reis A.,
RA Roepman R., Pasutto F.;
RT "Evidence for RPGRIP1 gene as risk factor for primary open angle
RT glaucoma.";
RL Eur. J. Hum. Genet. 19:445-451(2011).
RN [14]
RP FUNCTION, AND INTERACTION WITH INVS AND DVL2.
RX PubMed=21498478; DOI=10.1093/hmg/ddr164;
RA Burckle C., Gaude H.M., Vesque C., Silbermann F., Salomon R.,
RA Jeanpierre C., Antignac C., Saunier S., Schneider-Maunoury S.;
RT "Control of the Wnt pathways by nephrocystin-4 is required for
RT morphogenesis of the zebrafish pronephros.";
RL Hum. Mol. Genet. 20:2611-2627(2011).
RN [15]
RP FUNCTION, AND INTERACTION WITH LATS1.
RX PubMed=21555462; DOI=10.1083/jcb.201009069;
RA Habbig S., Bartram M.P., Mueller R.U., Schwarz R., Andriopoulos N.,
RA Chen S., Saegmueller J.G., Hoehne M., Burst V., Liebau M.C.,
RA Reinhardt H.C., Benzing T., Schermer B.;
RT "NPHP4, a cilia-associated protein, negatively regulates the Hippo
RT pathway.";
RL J. Cell Biol. 193:633-642(2011).
RN [16]
RP INVOLVEMENT IN CILIOPATHIES, AND VARIANT LEU-160.
RX PubMed=21258341; DOI=10.1038/ng.756;
RA Davis E.E., Zhang Q., Liu Q., Diplas B.H., Davey L.M., Hartley J.,
RA Stoetzel C., Szymanska K., Ramaswami G., Logan C.V., Muzny D.M.,
RA Young A.C., Wheeler D.A., Cruz P., Morgan M., Lewis L.R., Cherukuri P.,
RA Maskeri B., Hansen N.F., Mullikin J.C., Blakesley R.W., Bouffard G.G.,
RA Gyapay G., Rieger S., Tonshoff B., Kern I., Soliman N.A., Neuhaus T.J.,
RA Swoboda K.J., Kayserili H., Gallagher T.E., Lewis R.A., Bergmann C.,
RA Otto E.A., Saunier S., Scambler P.J., Beales P.L., Gleeson J.G.,
RA Maher E.R., Attie-Bitach T., Dollfus H., Johnson C.A., Green E.D.,
RA Gibbs R.A., Hildebrandt F., Pierce E.A., Katsanis N.;
RT "TTC21B contributes both causal and modifying alleles across the ciliopathy
RT spectrum.";
RL Nat. Genet. 43:189-196(2011).
RN [17]
RP INTERACTION WITH CEP164.
RX PubMed=22863007; DOI=10.1016/j.cell.2012.06.028;
RA Chaki M., Airik R., Ghosh A.K., Giles R.H., Chen R., Slaats G.G., Wang H.,
RA Hurd T.W., Zhou W., Cluckey A., Gee H.Y., Ramaswami G., Hong C.J.,
RA Hamilton B.A., Cervenka I., Ganji R.S., Bryja V., Arts H.H.,
RA van Reeuwijk J., Oud M.M., Letteboer S.J., Roepman R., Husson H.,
RA Ibraghimov-Beskrovnaya O., Yasunaga T., Walz G., Eley L., Sayer J.A.,
RA Schermer B., Liebau M.C., Benzing T., Le Corre S., Drummond I., Janssen S.,
RA Allen S.J., Natarajan S., O'Toole J.F., Attanasio M., Saunier S.,
RA Antignac C., Koenekoop R.K., Ren H., Lopez I., Nayir A., Stoetzel C.,
RA Dollfus H., Massoudi R., Gleeson J.G., Andreoli S.P., Doherty D.G.,
RA Lindstrad A., Golzio C., Katsanis N., Pape L., Abboud E.B., Al-Rajhi A.A.,
RA Lewis R.A., Omran H., Lee E.Y., Wang S., Sekiguchi J.M., Saunders R.,
RA Johnson C.A., Garner E., Vanselow K., Andersen J.S., Shlomai J.,
RA Nurnberg G., Nurnberg P., Levy S., Smogorzewska A., Otto E.A.,
RA Hildebrandt F.;
RT "Exome capture reveals ZNF423 and CEP164 mutations, linking renal
RT ciliopathies to DNA damage response signaling.";
RL Cell 150:533-548(2012).
RN [18]
RP POSSIBLE INVOLVEMENT IN HEART MALFORMATIONS, VARIANT NPHP4 TRP-1192,
RP VARIANT SLSN4 LEU-91, AND VARIANTS TYR-164; LEU-541; MET-883; CYS-906;
RP HIS-1044; VAL-1110 AND MET-1236.
RX PubMed=22550138; DOI=10.1161/circresaha.112.269795;
RA French V.M., van de Laar I.M., Wessels M.W., Rohe C., Roos-Hesselink J.W.,
RA Wang G., Frohn-Mulder I.M., Severijnen L.A., de Graaf B.M., Schot R.,
RA Breedveld G., Mientjes E., van Tienhoven M., Jadot E., Jiang Z.,
RA Verkerk A., Swagemakers S., Venselaar H., Rahimi Z., Najmabadi H.,
RA Meijers-Heijboer H., de Graaff E., Helbing W.A., Willemsen R.,
RA Devriendt K., Belmont J.W., Oostra B.A., Amack J.D., Bertoli-Avella A.M.;
RT "NPHP4 variants are associated with pleiotropic heart malformations.";
RL Circ. Res. 110:1564-1574(2012).
RN [19]
RP FUNCTION, INTERACTION WITH JADE1, AND SUBCELLULAR LOCATION.
RX PubMed=22654112; DOI=10.1074/jbc.m112.385658;
RA Borgal L., Habbig S., Hatzold J., Liebau M.C., Dafinger C., Sacarea I.,
RA Hammerschmidt M., Benzing T., Schermer B.;
RT "The ciliary protein nephrocystin-4 translocates the canonical Wnt
RT regulator Jade-1 to the nucleus to negatively regulate beta-catenin
RT signaling.";
RL J. Biol. Chem. 287:25370-25380(2012).
RN [20]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-142, AND IDENTIFICATION BY
RP 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 [21]
RP POSSIBLE INVOLVEMENT IN MALE INFERTILITY.
RX PubMed=23574405; DOI=10.1111/cge.12160;
RA Alazami A.M., Alshammari M.J., Baig M., Salih M.A., Hassan H.H.,
RA Alkuraya F.S.;
RT "NPHP4 mutation is linked to cerebello-oculo-renal syndrome and male
RT infertility.";
RL Clin. Genet. 85:371-375(2014).
RN [22]
RP INTERACTION WITH INTU AND DAAM1, AND SUBCELLULAR LOCATION.
RX PubMed=26644512; DOI=10.1083/jcb.201502043;
RA Yasunaga T., Hoff S., Schell C., Helmstaedter M., Kretz O., Kuechlin S.,
RA Yakulov T.A., Engel C., Mueller B., Bensch R., Ronneberger O., Huber T.B.,
RA Lienkamp S.S., Walz G.;
RT "The polarity protein Inturned links NPHP4 to Daam1 to control the
RT subapical actin network in multiciliated cells.";
RL J. Cell Biol. 211:963-973(2015).
RN [23]
RP VARIANTS NPHP4 CYS-342; TRP-469; GLY-654; TRP-735; ARG-766; ARG-776;
RP GLN-782; HIS-961; THR-1098; TRP-1192; CYS-1284 AND GLU-1287, VARIANTS SLSN4
RP TYR-3; LEU-91; MET-627; ALA-946 AND MET-1225, AND VARIANTS MET-29; GLY-544;
RP LYS-618; HIS-740; ILE-765; TRP-848 AND 940-ALA-GLN-941 DEL.
RX PubMed=15776426; DOI=10.1002/humu.9326;
RA Hoefele J., Sudbrak R., Reinhardt R., Lehrack S., Hennig S., Imm A.,
RA Muerb U., Utsch B., Attanasio M., O'Toole J.F., Otto E., Hildebrandt F.;
RT "Mutational analysis of the NPHP4 gene in 250 patients with
RT nephronophthisis.";
RL Hum. Mutat. 25:411-411(2005).
RN [24]
RP CHARACTERIZATION OF VARIANTS SLSN4 LEU-91.
RX PubMed=21546380; DOI=10.1093/hmg/ddr198;
RA Masyukova S.V., Winkelbauer M.E., Williams C.L., Pieczynski J.N.,
RA Yoder B.K.;
RT "Assessing the pathogenic potential of human Nephronophthisis disease-
RT associated NPHP-4 missense mutations in C. elegans.";
RL Hum. Mol. Genet. 20:2942-2954(2011).
RN [25]
RP VARIANT MET-315.
RX PubMed=26294103; DOI=10.1136/bjophthalmol-2015-307277;
RA Khan A.O., Eisenberger T., Nagel-Wolfrum K., Wolfrum U., Bolz H.J.;
RT "C21orf2 is mutated in recessive early-onset retinal dystrophy with macular
RT staphyloma and encodes a protein that localises to the photoreceptor
RT primary cilium.";
RL Br. J. Ophthalmol. 99:1725-1731(2015).
CC -!- FUNCTION: Involved in the organization of apical junctions; the
CC function is proposed to implicate a NPHP1-4-8 module (PubMed:19755384,
CC PubMed:21565611). Does not seem to be strictly required for
CC ciliogenesis (PubMed:21565611). Required for building functional cilia.
CC Involved in the organization of the subapical actin network in
CC multiciliated epithelial cells. Seems to recruit INT to basal bodies of
CC motile cilia which subsequently interacts with actin-modifying proteins
CC such as DAAM1 (By similarity). In cooperation with INVS may down-
CC regulate the canonical Wnt pathway and promote the Wnt-PCP pathway by
CC regulating expression and subcellular location of disheveled proteins.
CC Stabilizes protein levels of JADE1 and promotes its translocation to
CC the nucleus leading to cooperative inhibition of canonical Wnt
CC signaling (PubMed:21498478, PubMed:22654112). Acts as negative
CC regulator of the hippo pathway by association with LATS1 and modifying
CC LATS1-dependent phosphorylation and localization of WWTR1/TAZ
CC (PubMed:21555462). {ECO:0000250|UniProtKB:B0DOB4,
CC ECO:0000250|UniProtKB:P59240, ECO:0000269|PubMed:21498478,
CC ECO:0000269|PubMed:21555462, ECO:0000269|PubMed:21565611,
CC ECO:0000269|PubMed:22654112, ECO:0000305|PubMed:19755384}.
CC -!- SUBUNIT: Interacts with NPHP1 (PubMed:15661758). Interacts with NPHP1
CC and RPGRIP1L/NPHP8; NPHP1, NPHP4 and RPGRIP1L are proposed to form a
CC functional NPHP1-4-8 module localized to cell-cell contacts and the
CC ciliary transition zone; NPHP4 mediates the interaction between NPHP1
CC and RPGRIP1L. Interacts with IQCB1/NPHP5; the interaction likely
CC requires additional interactors (By similarity). Interacts with
CC RPGRIP1, CEP164, JADE1, PALS1, INADL, PARD6A, INVS, DVL2, LATS1.
CC Interacts with INTU; INTU mediates the interaction between NPHP4 and
CC DAAM1 (PubMed:26644512). Interacts with SPATA7 (By similarity).
CC {ECO:0000250|UniProtKB:P59240, ECO:0000269|PubMed:12244321,
CC ECO:0000269|PubMed:15661758, ECO:0000269|PubMed:16339905,
CC ECO:0000269|PubMed:17558407, ECO:0000269|PubMed:19755384,
CC ECO:0000269|PubMed:21224891, ECO:0000269|PubMed:21498478,
CC ECO:0000269|PubMed:21555462, ECO:0000269|PubMed:22654112,
CC ECO:0000269|PubMed:22863007, ECO:0000269|PubMed:26644512}.
CC -!- INTERACTION:
CC O75161; Q9ULD6: INTU; NbExp=2; IntAct=EBI-4281852, EBI-11762696;
CC O75161; Q6IE81: JADE1; NbExp=4; IntAct=EBI-4281852, EBI-954672;
CC O75161; O15259: NPHP1; NbExp=18; IntAct=EBI-4281852, EBI-953828;
CC O75161; Q14289: PTK2B; NbExp=2; IntAct=EBI-4281852, EBI-298640;
CC O75161; Q96KN7: RPGRIP1; NbExp=3; IntAct=EBI-4281852, EBI-1050213;
CC O75161; Q68CZ1-2: RPGRIP1L; NbExp=8; IntAct=EBI-4281852, EBI-9356215;
CC O75161; Q9Y265: RUVBL1; NbExp=2; IntAct=EBI-4281852, EBI-353675;
CC O75161-1; Q96KN7-1: RPGRIP1; NbExp=9; IntAct=EBI-12499345, EBI-12499377;
CC -!- SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton, cilium basal body
CC {ECO:0000269|PubMed:17558407, ECO:0000269|PubMed:26644512}. Cytoplasm,
CC cytoskeleton, microtubule organizing center, centrosome
CC {ECO:0000269|PubMed:17558407}. Cell junction, tight junction
CC {ECO:0000250|UniProtKB:P59240}. Nucleus {ECO:0000269|PubMed:22654112}.
CC Note=In cultured renal cells, it localizes diffusely in the cytoplasm
CC but, as cells approach confluence, it accumulates to basolateral tight
CC junctions (By similarity). Localizes to the ciliary transition zone (By
CC similarity). In the retinal photoreceptor cell layer, localizes at the
CC connecting cilium (By similarity). {ECO:0000250|UniProtKB:P59240}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=1;
CC IsoId=O75161-1; Sequence=Displayed;
CC Name=2;
CC IsoId=O75161-2; Sequence=VSP_054514, VSP_054515, VSP_054516;
CC -!- TISSUE SPECIFICITY: Expressed in kidney, skeletal muscle, heart and
CC liver, and to a lesser extent in brain and lung.
CC {ECO:0000269|PubMed:12244321}.
CC -!- DISEASE: Nephronophthisis 4 (NPHP4) [MIM:606966]: An autosomal
CC recessive inherited disease resulting in end-stage renal disease at age
CC ranging between 6 and 35 years. It is a progressive tubulo-interstitial
CC kidney disorder characterized by polydipsia, polyuria, anemia and
CC growth retardation. The most prominent histological features are
CC modifications of the tubules with thickening of the basement membrane,
CC interstitial fibrosis and, in the advanced stages, medullary cysts.
CC {ECO:0000269|PubMed:12205563, ECO:0000269|PubMed:12244321,
CC ECO:0000269|PubMed:15776426, ECO:0000269|PubMed:16339905,
CC ECO:0000269|PubMed:17558407, ECO:0000269|PubMed:22550138}. Note=The
CC disease is caused by variants affecting the gene represented in this
CC entry.
CC -!- DISEASE: Note=Ciliary dysfunction leads to a broad spectrum of
CC disorders, collectively termed ciliopathies. Overlapping clinical
CC features include retinal degeneration, renal cystic disease, skeletal
CC abnormalities, fibrosis of various organ, and a complex range of
CC anatomical and functional defects of the central and peripheral nervous
CC system. The ciliopathy range of diseases includes Meckel-Gruber
CC syndrome, Bardet-Biedl syndrome, Joubert syndrome, nephronophtisis,
CC Senior-Loken syndrome, and Jeune asphyxiating thoracic dystrophy among
CC others. Single-locus allelism is insufficient to explain the variable
CC penetrance and expressivity of such disorders, leading to the
CC suggestion that variations across multiple sites of the ciliary
CC proteome, including NPHP4, influence the clinical outcome
CC (PubMed:21258341). {ECO:0000269|PubMed:21258341}.
CC -!- DISEASE: Senior-Loken syndrome 4 (SLSN4) [MIM:606996]: A renal-retinal
CC disorder characterized by progressive wasting of the filtering unit of
CC the kidney (nephronophthisis), with or without medullary cystic renal
CC disease, and progressive eye disease. Typically this disorder becomes
CC apparent during the first year of life. {ECO:0000269|PubMed:12244321,
CC ECO:0000269|PubMed:15776426, ECO:0000269|PubMed:21546380,
CC ECO:0000269|PubMed:22550138}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Note=May be involved in male infertility. Homozygosity for a
CC frameshift truncating mutation are associated with markedly abnormal
CC sperm morphology. {ECO:0000269|PubMed:23574405}.
CC -!- DISEASE: Note=May be involved in cardiac laterality defects and
CC heterotaxy. {ECO:0000305|PubMed:22550138}.
CC -!- SIMILARITY: Belongs to the NPHP4 family. {ECO:0000305}.
CC ---------------------------------------------------------------------------
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DR EMBL; AY118228; AAM78558.1; -; mRNA.
DR EMBL; AF537130; AAN06814.1; -; mRNA.
DR EMBL; AL035406; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL356261; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; AL356693; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR EMBL; CH471130; EAW71509.1; -; Genomic_DNA.
DR EMBL; BC040520; AAH40520.1; -; mRNA.
DR EMBL; AB014573; BAA31648.1; -; mRNA.
DR CCDS; CCDS44052.1; -. [O75161-1]
DR PIR; T00364; T00364.
DR RefSeq; NP_001278522.1; NM_001291593.1.
DR RefSeq; NP_001278523.1; NM_001291594.1.
DR RefSeq; NP_055917.1; NM_015102.4. [O75161-1]
DR RefSeq; XP_006710626.1; XM_006710563.3. [O75161-1]
DR RefSeq; XP_011539518.1; XM_011541216.2. [O75161-1]
DR RefSeq; XP_011539519.1; XM_011541217.2. [O75161-1]
DR RefSeq; XP_011539520.1; XM_011541218.2. [O75161-1]
DR RefSeq; XP_016856486.1; XM_017000997.1. [O75161-1]
DR AlphaFoldDB; O75161; -.
DR BioGRID; 129286; 70.
DR CORUM; O75161; -.
DR IntAct; O75161; 88.
DR MINT; O75161; -.
DR STRING; 9606.ENSP00000367398; -.
DR iPTMnet; O75161; -.
DR PhosphoSitePlus; O75161; -.
DR BioMuta; NPHP4; -.
DR EPD; O75161; -.
DR jPOST; O75161; -.
DR MassIVE; O75161; -.
DR MaxQB; O75161; -.
DR PaxDb; O75161; -.
DR PeptideAtlas; O75161; -.
DR PRIDE; O75161; -.
DR ProteomicsDB; 49828; -. [O75161-1]
DR ProteomicsDB; 70841; -.
DR Antibodypedia; 27030; 124 antibodies from 24 providers.
DR DNASU; 261734; -.
DR Ensembl; ENST00000378156.9; ENSP00000367398.4; ENSG00000131697.18. [O75161-1]
DR Ensembl; ENST00000489180.6; ENSP00000423747.1; ENSG00000131697.18. [O75161-2]
DR Ensembl; ENST00000622020.4; ENSP00000481831.2; ENSG00000131697.18. [O75161-2]
DR GeneID; 261734; -.
DR KEGG; hsa:261734; -.
DR MANE-Select; ENST00000378156.9; ENSP00000367398.4; NM_015102.5; NP_055917.1.
DR UCSC; uc001alq.3; human. [O75161-1]
DR CTD; 261734; -.
DR DisGeNET; 261734; -.
DR GeneCards; NPHP4; -.
DR GeneReviews; NPHP4; -.
DR HGNC; HGNC:19104; NPHP4.
DR HPA; ENSG00000131697; Low tissue specificity.
DR MalaCards; NPHP4; -.
DR MIM; 606966; phenotype.
DR MIM; 606996; phenotype.
DR MIM; 607215; gene.
DR neXtProt; NX_O75161; -.
DR OpenTargets; ENSG00000131697; -.
DR Orphanet; 93592; Juvenile nephronophthisis.
DR Orphanet; 3156; Senior-Loken syndrome.
DR PharmGKB; PA134927048; -.
DR VEuPathDB; HostDB:ENSG00000131697; -.
DR eggNOG; ENOG502QUNP; Eukaryota.
DR GeneTree; ENSGT00510000048827; -.
DR HOGENOM; CLU_004882_0_0_1; -.
DR InParanoid; O75161; -.
DR OMA; HVPFKFQ; -.
DR OrthoDB; 53958at2759; -.
DR PhylomeDB; O75161; -.
DR TreeFam; TF351573; -.
DR PathwayCommons; O75161; -.
DR Reactome; R-HSA-2028269; Signaling by Hippo.
DR Reactome; R-HSA-5620912; Anchoring of the basal body to the plasma membrane.
DR SignaLink; O75161; -.
DR BioGRID-ORCS; 261734; 6 hits in 1077 CRISPR screens.
DR ChiTaRS; NPHP4; human.
DR GeneWiki; NPHP4; -.
DR GenomeRNAi; 261734; -.
DR Pharos; O75161; Tbio.
DR PRO; PR:O75161; -.
DR Proteomes; UP000005640; Chromosome 1.
DR RNAct; O75161; protein.
DR Bgee; ENSG00000131697; Expressed in right uterine tube and 90 other tissues.
DR ExpressionAtlas; O75161; baseline and differential.
DR Genevisible; O75161; HS.
DR GO; GO:0005923; C:bicellular tight junction; IEA:UniProtKB-SubCell.
DR GO; GO:0005911; C:cell-cell junction; IDA:UniProtKB.
DR GO; GO:0005814; C:centriole; IEA:Ensembl.
DR GO; GO:0005813; C:centrosome; IDA:UniProtKB.
DR GO; GO:0036064; C:ciliary basal body; IBA:GO_Central.
DR GO; GO:0097546; C:ciliary base; IBA:GO_Central.
DR GO; GO:0035869; C:ciliary transition zone; IBA:GO_Central.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:HPA.
DR GO; GO:0097730; C:non-motile cilium; IBA:GO_Central.
DR GO; GO:0016604; C:nuclear body; IDA:HPA.
DR GO; GO:0005654; C:nucleoplasm; IDA:HPA.
DR GO; GO:0120206; C:photoreceptor distal connecting cilium; IEA:Ensembl.
DR GO; GO:0097470; C:ribbon synapse; IEA:Ensembl.
DR GO; GO:0005198; F:structural molecule activity; NAS:UniProtKB.
DR GO; GO:0030036; P:actin cytoskeleton organization; NAS:UniProtKB.
DR GO; GO:0098609; P:cell-cell adhesion; NAS:UniProtKB.
DR GO; GO:0030317; P:flagellated sperm motility; IEA:Ensembl.
DR GO; GO:0090090; P:negative regulation of canonical Wnt signaling pathway; IDA:UniProtKB.
DR GO; GO:0045494; P:photoreceptor cell maintenance; IEA:Ensembl.
DR GO; GO:0035845; P:photoreceptor cell outer segment organization; IEA:Ensembl.
DR GO; GO:1903348; P:positive regulation of bicellular tight junction assembly; IMP:UniProtKB.
DR GO; GO:1904491; P:protein localization to ciliary transition zone; IBA:GO_Central.
DR GO; GO:0060041; P:retina development in camera-type eye; IEA:Ensembl.
DR GO; GO:0007165; P:signal transduction; NAS:UniProtKB.
DR GO; GO:0007632; P:visual behavior; NAS:UniProtKB.
DR InterPro; IPR029775; NPHP4.
DR PANTHER; PTHR31043; PTHR31043; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Cell junction; Cell projection; Ciliopathy; Cilium;
KW Cytoplasm; Cytoskeleton; Disease variant; Leber congenital amaurosis;
KW Nephronophthisis; Nucleus; Phosphoprotein; Reference proteome;
KW Senior-Loken syndrome; Tight junction.
FT CHAIN 1..1426
FT /note="Nephrocystin-4"
FT /id="PRO_0000159769"
FT REGION 450..536
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 823..1426
FT /note="Sufficient for basal bodies localization"
FT /evidence="ECO:0000269|PubMed:26644512"
FT REGION 896..935
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 475..490
FT /note="Pro residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 498..536
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 900..924
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 142
FT /note="Phosphoserine"
FT /evidence="ECO:0007744|PubMed:23186163"
FT VAR_SEQ 538
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_054514"
FT VAR_SEQ 872..912
FT /note="KHVVQAQKLADVDSELAAMLLTHARQGKGPQDVSRESDATR -> WALQATV
FT LFGEVGTLPVAFVSGWLLICKGRRNGEKVRRNID (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_054515"
FT VAR_SEQ 913..1426
FT /note="Missing (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_054516"
FT VARIANT 3
FT /note="D -> Y (in SLSN4; dbSNP:rs145078518)"
FT /evidence="ECO:0000269|PubMed:15776426"
FT /id="VAR_022526"
FT VARIANT 29
FT /note="T -> M (in dbSNP:rs12142270)"
FT /evidence="ECO:0000269|PubMed:15776426"
FT /id="VAR_022527"
FT VARIANT 91
FT /note="F -> L (in SLSN4; also found in a patient with
FT cardiac laterality defects; impairs localization to the
FT ciliary transition zone; dbSNP:rs201065230)"
FT /evidence="ECO:0000269|PubMed:15776426,
FT ECO:0000269|PubMed:22550138, ECO:0000305|PubMed:21546380"
FT /id="VAR_022528"
FT VARIANT 160
FT /note="R -> L (in a patient with nephronophthisis with
FT extra-renal features; the patient also carries W-735 in the
FT same gene and L-209 in TTC21B)"
FT /evidence="ECO:0000269|PubMed:21258341"
FT /id="VAR_065557"
FT VARIANT 164
FT /note="H -> Y (found in a patient with cardiac laterality
FT defects; unknown pathological significance;
FT dbSNP:rs761063669)"
FT /evidence="ECO:0000269|PubMed:22550138"
FT /id="VAR_076785"
FT VARIANT 315
FT /note="T -> M (in dbSNP:rs200684272)"
FT /evidence="ECO:0000269|PubMed:26294103"
FT /id="VAR_079179"
FT VARIANT 342
FT /note="R -> C (in NPHP4; dbSNP:rs190940697)"
FT /evidence="ECO:0000269|PubMed:15776426"
FT /id="VAR_022529"
FT VARIANT 469
FT /note="R -> W (in NPHP4; dbSNP:rs758253306)"
FT /evidence="ECO:0000269|PubMed:15776426"
FT /id="VAR_022530"
FT VARIANT 541
FT /note="P -> L (found in a patient with cardiac laterality
FT defects; unknown pathological significance;
FT dbSNP:rs145255635)"
FT /evidence="ECO:0000269|PubMed:22550138"
FT /id="VAR_076786"
FT VARIANT 544
FT /note="A -> G (in dbSNP:rs12093500)"
FT /evidence="ECO:0000269|PubMed:15776426"
FT /id="VAR_022531"
FT VARIANT 618
FT /note="E -> K (in dbSNP:rs571655)"
FT /evidence="ECO:0000269|PubMed:15776426"
FT /id="VAR_022532"
FT VARIANT 627
FT /note="T -> M (in SLSN4; dbSNP:rs199891059)"
FT /evidence="ECO:0000269|PubMed:15776426"
FT /id="VAR_022533"
FT VARIANT 654
FT /note="A -> G (in NPHP4)"
FT /evidence="ECO:0000269|PubMed:15776426"
FT /id="VAR_022534"
FT VARIANT 735
FT /note="R -> W (in NPHP4; dbSNP:rs191913664)"
FT /evidence="ECO:0000269|PubMed:15776426"
FT /id="VAR_022535"
FT VARIANT 740
FT /note="R -> H (does not affect interaction with RPGRIP1L;
FT does not affect interaction with RPGRIP1;
FT dbSNP:rs34248917)"
FT /evidence="ECO:0000269|PubMed:15776426,
FT ECO:0000269|PubMed:16339905, ECO:0000269|PubMed:17558407"
FT /id="VAR_022536"
FT VARIANT 754
FT /note="G -> R (in NPHP4; affects interaction with RPGRIP1L;
FT disrupts interaction with RPGRIP1; dbSNP:rs373962831)"
FT /evidence="ECO:0000269|PubMed:12205563,
FT ECO:0000269|PubMed:16339905, ECO:0000269|PubMed:17558407"
FT /id="VAR_015214"
FT VARIANT 765
FT /note="V -> I (in dbSNP:rs149244006)"
FT /evidence="ECO:0000269|PubMed:15776426"
FT /id="VAR_022537"
FT VARIANT 766
FT /note="Q -> R (in NPHP4; with color blindness)"
FT /evidence="ECO:0000269|PubMed:15776426"
FT /id="VAR_022538"
FT VARIANT 776
FT /note="P -> R (in NPHP4; dbSNP:rs201527181)"
FT /evidence="ECO:0000269|PubMed:15776426"
FT /id="VAR_022539"
FT VARIANT 782
FT /note="H -> Q (in NPHP4; dbSNP:rs1433852047)"
FT /evidence="ECO:0000269|PubMed:15776426"
FT /id="VAR_022540"
FT VARIANT 848
FT /note="R -> W (does not affect interaction with RPGRIP1L;
FT does not affect interaction with RPGRIP1;
FT dbSNP:rs17472401)"
FT /evidence="ECO:0000269|PubMed:12205563,
FT ECO:0000269|PubMed:15776426, ECO:0000269|PubMed:16339905,
FT ECO:0000269|PubMed:17558407"
FT /id="VAR_015215"
FT VARIANT 883
FT /note="V -> M (found in a patient with cardiac laterality
FT defects; unknown pathological significance;
FT dbSNP:rs769851221)"
FT /evidence="ECO:0000269|PubMed:22550138"
FT /id="VAR_076787"
FT VARIANT 906
FT /note="R -> C (found in a patient with cardiac laterality
FT defects; unknown pathological significance;
FT dbSNP:rs199992272)"
FT /evidence="ECO:0000269|PubMed:22550138"
FT /id="VAR_076788"
FT VARIANT 939
FT /note="L -> Q (in dbSNP:rs1287637)"
FT /id="VAR_037622"
FT VARIANT 940..941
FT /note="Missing"
FT /evidence="ECO:0000269|PubMed:15776426"
FT /id="VAR_022541"
FT VARIANT 946
FT /note="T -> A (in SLSN4)"
FT /evidence="ECO:0000269|PubMed:15776426"
FT /id="VAR_022542"
FT VARIANT 959
FT /note="R -> Q (in dbSNP:rs12084067)"
FT /id="VAR_037623"
FT VARIANT 961
FT /note="R -> H (in NPHP4; benign variant;
FT dbSNP:rs183885357)"
FT /evidence="ECO:0000269|PubMed:15776426"
FT /id="VAR_022543"
FT VARIANT 991
FT /note="F -> S (in NPHP4; dbSNP:rs28940891)"
FT /evidence="ECO:0000269|PubMed:12244321"
FT /id="VAR_015186"
FT VARIANT 1044
FT /note="R -> H (found in a patient with cardiac laterality
FT defects; fails to rescue heart looping defects in zebrafish
FT knockout; dbSNP:rs375819124)"
FT /evidence="ECO:0000269|PubMed:22550138"
FT /id="VAR_076789"
FT VARIANT 1098
FT /note="A -> T (in NPHP4; dbSNP:rs41280798)"
FT /evidence="ECO:0000269|PubMed:15776426"
FT /id="VAR_022544"
FT VARIANT 1110
FT /note="A -> V (found in a patient with cardiac laterality
FT defects; unknown pathological significance;
FT dbSNP:rs139767853)"
FT /evidence="ECO:0000269|PubMed:22550138"
FT /id="VAR_076790"
FT VARIANT 1192
FT /note="R -> W (in NPHP4; also found in a patient with
FT cardiac laterality defects; dbSNP:rs139022622)"
FT /evidence="ECO:0000269|PubMed:15776426,
FT ECO:0000269|PubMed:22550138"
FT /id="VAR_022545"
FT VARIANT 1225
FT /note="T -> M (in SLSN4; benign variant;
FT dbSNP:rs144624477)"
FT /evidence="ECO:0000269|PubMed:15776426"
FT /id="VAR_022546"
FT VARIANT 1236
FT /note="V -> M (found in a patient with cardiac laterality
FT defects; fails to rescue heart looping defects in zebrafish
FT knockout; dbSNP:rs781049266)"
FT /evidence="ECO:0000269|PubMed:22550138"
FT /id="VAR_076791"
FT VARIANT 1284
FT /note="R -> C (in NPHP4; dbSNP:rs779755743)"
FT /evidence="ECO:0000269|PubMed:15776426"
FT /id="VAR_022547"
FT VARIANT 1287
FT /note="Q -> E (in NPHP4; with hearing loss;
FT dbSNP:rs201779243)"
FT /evidence="ECO:0000269|PubMed:15776426"
FT /id="VAR_022548"
SQ SEQUENCE 1426 AA; 157598 MW; 8C974278F4EE4505 CRC64;
MNDWHRIFTQ NVLVPPHPQR ARQPWKESTA FQCVLKWLDG PVIRQGVLEV LSEVECHLRV
SFFDVTYRHF FGRTWKTTVK PTKRPPSRIV FNEPLYFHTS LNHPHIVAVV EVVAEGKKRD
GSLQTLSCGF GILRIFSNQP DSPISASQDK RLRLYHGTPR ALLHPLLQDP AEQNRHMTLI
ENCSLQYTLK PHPALEPAFH LLPENLLVSG LQQIPGLLPA HGESGDALRK PRLQKPITGH
LDDLFFTLYP SLEKFEEELL ELHVQDHFQE GCGPLDGGAL EILERRLRVG VHNGLGFVQR
PQVVVLVPEM DVALTRSASF SRKVVSSSKT SSGSQALVLR SRLRLPEMVG HPAFAVIFQL
EYVFSSPAGV DGNAASVTSL SNLACMHMVR WAVWNPLLEA DSGRVTLPLQ GGIQPNPSHC
LVYKVPSASM SSEEVKQVES GTLRFQFSLG SEEHLDAPTE PVSGPKVERR PSRKPPTSPS
SPPAPVPRVL AAPQNSPVGP GLSISQLAAS PRSPTQHCLA RPTSQLPHGS QASPAQAQEF
PLEAGISHLE ADLSQTSLVL ETSIAEQLQE LPFTPLHAPI VVGTQTRSSA GQPSRASMVL
LQSSGFPEIL DANKQPAEAV SATEPVTFNP QKEESDCLQS NEMVLQFLAF SRVAQDCRGT
SWPKTVYFTF QFYRFPPATT PRLQLVQLDE AGQPSSGALT HILVPVSRDG TFDAGSPGFQ
LRYMVGPGFL KPGERRCFAR YLAVQTLQID VWDGDSLLLI GSAAVQMKHL LRQGRPAVQA
SHELEVVATE YEQDNMVVSG DMLGFGRVKP IGVHSVVKGR LHLTLANVGH PCEQKVRGCS
TLPPSRSRVI SNDGASRFSG GSLLTTGSSR RKHVVQAQKL ADVDSELAAM LLTHARQGKG
PQDVSRESDA TRRRKLERMR SVRLQEAGGD LGRRGTSVLA QQSVRTQHLR DLQVIAAYRE
RTKAESIASL LSLAITTEHT LHATLGVAEF FEFVLKNPHN TQHTVTVEID NPELSVIVDS
QEWRDFKGAA GLHTPVEEDM FHLRGSLAPQ LYLRPHETAH VPFKFQSFSA GQLAMVQASP
GLSNEKGMDA VSPWKSSAVP TKHAKVLFRA SGGKPIAVLC LTVELQPHVV DQVFRFYHPE
LSFLKKAIRL PPWHTFPGAP VGMLGEDPPV HVRCSDPNVI CETQNVGPGE PRDIFLKVAS
GPSPEIKDFF VIIYSDRWLA TPTQTWQVYL HSLQRVDVSC VAGQLTRLSL VLRGTQTVRK
VRAFTSHPQE LKTDPKGVFV LPPRGVQDLH VGVRPLRAGS RFVHLNLVDV DCHQLVASWL
VCLCCRQPLI SKAFEIMLAA GEGKGVNKRI TYTNPYPSRR TFHLHSDHPE LLRFREDSFQ
VGGGETYTIG LQFAPSQRVG EEEILIYIND HEDKNEEAFC VKVIYQ
