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 27-MAR-2024, entry version 180. 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 a 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 --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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. DR RefSeq; XP_016856486.1; XM_017000997.1. DR AlphaFoldDB; O75161; -. DR BioGRID; 129286; 72. DR ComplexPortal; CPX-2806; NPHP transition zone complex. 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; 9606-ENSP00000367398; -. DR PeptideAtlas; O75161; -. DR ProteomicsDB; 49828; -. [O75161-1] DR ProteomicsDB; 70841; -. DR Antibodypedia; 27030; 145 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 AGR; HGNC:19104; -. 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; FLLEYTF; -. DR OrthoDB; 313695at2759; -. 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 1155 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 92 other cell types or tissues. DR ExpressionAtlas; O75161; baseline and differential. 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 CDD; cd22239; NPHP4; 1. DR InterPro; IPR029775; NPHP4. DR PANTHER; PTHR31043; NEPHROCYSTIN-4; 1. DR PANTHER; PTHR31043:SF3; NEPHROCYSTIN-4; 1. DR Genevisible; O75161; HS. 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; uncertain significance; 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; uncertain significance; 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; uncertain significance; 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; uncertain significance; 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; 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; uncertain significance; 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; 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 //