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O75161 (NPHP4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 105. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (5) | Third-party data text xml rdf/xml gff fasta
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Names and origin

Protein namesRecommended name:
Nephrocystin-4
Alternative name(s):
Nephroretinin
Gene names
Name:NPHP4
Synonyms:KIAA0673
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length1426 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

Involved in the organization of apical junctions in kidney cells together with NPHP1 and RPGRIP1L/NPHP8 By similarity. Does not seem to be strictly required for ciliogenesis By similarity.

Subunit structure

Interacts with NPHP1 and RPGRIP1L/NPHP8, and can bridge the interaction between those two proteins. Interacts with IQCB1; the interaction likely requires additional interactors. Interacts with RPGRIP1. Weakly interacts with CEP164. Ref.1 Ref.5 Ref.6 Ref.7 Ref.9

Subcellular location

Cytoplasmcytoskeletoncilium basal body. Cytoplasmcytoskeletonmicrotubule organizing centercentrosome. Cell junctiontight junction. Note: In cultured renal cells, it localizes diffusely in the cytoplasm but, as cells approach confluence, it accumulates to basolateral tight junctions. Ref.5 Ref.6

Tissue specificity

Expressed in kidney, skeletal muscle, heart and liver, and to a lesser extent in brain and lung. Ref.1

Involvement in disease

Nephronophthisis 4 (NPHP4) [MIM:606966]: An autosomal recessive inherited disease resulting in end-stage renal disease at age ranging between 6 and 35 years. It is a progressive tubulo-interstitial kidney disorder characterized by polydipsia, polyuria, anemia and growth retardation. The most prominent histological features are modifications of the tubules with thickening of the basement membrane, interstitial fibrosis and, in the advanced stages, medullary cysts.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.1 Ref.3 Ref.5 Ref.10

Ciliary dysfunction leads to a broad spectrum of disorders, collectively termed ciliopathies. Overlapping clinical features include retinal degeneration, renal cystic disease, skeletal abnormalities, fibrosis of various organ, and a complex range of anatomical and functional defects of the central and peripheral nervous system. The ciliopathy range of diseases includes Meckel-Gruber syndrome, Bardet-Biedl syndrome, Joubert syndrome, nephronophtisis, Senior-Loken syndrome, and Jeune asphyxiating thoracic dystrophy among others. Single-locus allelism is insufficient to explain the variable penetrance and expressivity of such disorders, leading to the suggestion that variations across multiple sites of the ciliary proteome, including NPHP4, influence the clinical outcome.

Senior-Loken syndrome 4 (SLSN4) [MIM:606996]: A renal-retinal disorder characterized by progressive wasting of the filtering unit of the kidney (nephronophthisis), with or without medullary cystic renal disease, and progressive eye disease. Typically this disorder becomes apparent during the first year of life.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.1 Ref.10

Sequence similarities

Belongs to the NPHP4 family.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 14261426Nephrocystin-4
PRO_0000159769

Natural variations

Natural variant31D → Y in SLSN4. Ref.10
Corresponds to variant rs145078518 [ dbSNP | Ensembl ].
VAR_022526
Natural variant291T → M. Ref.10
Corresponds to variant rs12142270 [ dbSNP | Ensembl ].
VAR_022527
Natural variant911F → L in SLSN4. Ref.10
VAR_022528
Natural variant1601R → L in a patient with nephronophthisis with extra-renal features; the patient also carries W-735 in the same gene and L-209 in TTC21B. Ref.8
VAR_065557
Natural variant3421R → C in NPHP4. Ref.10
Corresponds to variant rs190940697 [ dbSNP | Ensembl ].
VAR_022529
Natural variant4691R → W in NPHP4. Ref.10
VAR_022530
Natural variant5441A → G. Ref.10
Corresponds to variant rs12093500 [ dbSNP | Ensembl ].
VAR_022531
Natural variant6181E → K. Ref.10
Corresponds to variant rs571655 [ dbSNP | Ensembl ].
VAR_022532
Natural variant6271T → M in SLSN4. Ref.10
Corresponds to variant rs199891059 [ dbSNP | Ensembl ].
VAR_022533
Natural variant6541A → G in NPHP4. Ref.10
VAR_022534
Natural variant7351R → W in NPHP4. Ref.10
Corresponds to variant rs191913664 [ dbSNP | Ensembl ].
VAR_022535
Natural variant7401R → H Does not affect interaction with RPGRIP1L. Ref.5 Ref.10
Corresponds to variant rs34248917 [ dbSNP | Ensembl ].
VAR_022536
Natural variant7541G → R in NPHP4; affects interaction with RPGRIP1L. Ref.3 Ref.5
VAR_015214
Natural variant7651V → I. Ref.10
Corresponds to variant rs149244006 [ dbSNP | Ensembl ].
VAR_022537
Natural variant7661Q → R in NPHP4; with color blindness. Ref.10
VAR_022538
Natural variant7761P → R in NPHP4. Ref.10
Corresponds to variant rs201527181 [ dbSNP | Ensembl ].
VAR_022539
Natural variant7821H → Q in NPHP4. Ref.10
VAR_022540
Natural variant8481R → W Does not affect interaction with RPGRIP1L. Ref.3 Ref.5 Ref.10
Corresponds to variant rs17472401 [ dbSNP | Ensembl ].
VAR_015215
Natural variant9391L → Q.
Corresponds to variant rs1287637 [ dbSNP | Ensembl ].
VAR_037622
Natural variant940 – 9412Missing.
VAR_022541
Natural variant9461T → A in SLSN4. Ref.10
VAR_022542
Natural variant9591R → Q.
Corresponds to variant rs12084067 [ dbSNP | Ensembl ].
VAR_037623
Natural variant9611R → H in NPHP4. Ref.10
Corresponds to variant rs183885357 [ dbSNP | Ensembl ].
VAR_022543
Natural variant9911F → S in NPHP4. Ref.1
Corresponds to variant rs28940891 [ dbSNP | Ensembl ].
VAR_015186
Natural variant10981A → T in NPHP4. Ref.10
Corresponds to variant rs41280798 [ dbSNP | Ensembl ].
VAR_022544
Natural variant11921R → W in NPHP4. Ref.10
Corresponds to variant rs139022622 [ dbSNP | Ensembl ].
VAR_022545
Natural variant12251T → M in SLSN4. Ref.10
Corresponds to variant rs144624477 [ dbSNP | Ensembl ].
VAR_022546
Natural variant12841R → C in NPHP4. Ref.10
VAR_022547
Natural variant12871Q → E in NPHP4; with hearing loss. Ref.10
VAR_022548

Sequences

Sequence LengthMass (Da)Tools
O75161 [UniParc].

Last modified January 27, 2003. Version 2.
Checksum: 8C974278F4EE4505

FASTA1,426157,598
        10         20         30         40         50         60 
MNDWHRIFTQ NVLVPPHPQR ARQPWKESTA FQCVLKWLDG PVIRQGVLEV LSEVECHLRV 

        70         80         90        100        110        120 
SFFDVTYRHF FGRTWKTTVK PTKRPPSRIV FNEPLYFHTS LNHPHIVAVV EVVAEGKKRD 

       130        140        150        160        170        180 
GSLQTLSCGF GILRIFSNQP DSPISASQDK RLRLYHGTPR ALLHPLLQDP AEQNRHMTLI 

       190        200        210        220        230        240 
ENCSLQYTLK PHPALEPAFH LLPENLLVSG LQQIPGLLPA HGESGDALRK PRLQKPITGH 

       250        260        270        280        290        300 
LDDLFFTLYP SLEKFEEELL ELHVQDHFQE GCGPLDGGAL EILERRLRVG VHNGLGFVQR 

       310        320        330        340        350        360 
PQVVVLVPEM DVALTRSASF SRKVVSSSKT SSGSQALVLR SRLRLPEMVG HPAFAVIFQL 

       370        380        390        400        410        420 
EYVFSSPAGV DGNAASVTSL SNLACMHMVR WAVWNPLLEA DSGRVTLPLQ GGIQPNPSHC 

       430        440        450        460        470        480 
LVYKVPSASM SSEEVKQVES GTLRFQFSLG SEEHLDAPTE PVSGPKVERR PSRKPPTSPS 

       490        500        510        520        530        540 
SPPAPVPRVL AAPQNSPVGP GLSISQLAAS PRSPTQHCLA RPTSQLPHGS QASPAQAQEF 

       550        560        570        580        590        600 
PLEAGISHLE ADLSQTSLVL ETSIAEQLQE LPFTPLHAPI VVGTQTRSSA GQPSRASMVL 

       610        620        630        640        650        660 
LQSSGFPEIL DANKQPAEAV SATEPVTFNP QKEESDCLQS NEMVLQFLAF SRVAQDCRGT 

       670        680        690        700        710        720 
SWPKTVYFTF QFYRFPPATT PRLQLVQLDE AGQPSSGALT HILVPVSRDG TFDAGSPGFQ 

       730        740        750        760        770        780 
LRYMVGPGFL KPGERRCFAR YLAVQTLQID VWDGDSLLLI GSAAVQMKHL LRQGRPAVQA 

       790        800        810        820        830        840 
SHELEVVATE YEQDNMVVSG DMLGFGRVKP IGVHSVVKGR LHLTLANVGH PCEQKVRGCS 

       850        860        870        880        890        900 
TLPPSRSRVI SNDGASRFSG GSLLTTGSSR RKHVVQAQKL ADVDSELAAM LLTHARQGKG 

       910        920        930        940        950        960 
PQDVSRESDA TRRRKLERMR SVRLQEAGGD LGRRGTSVLA QQSVRTQHLR DLQVIAAYRE 

       970        980        990       1000       1010       1020 
RTKAESIASL LSLAITTEHT LHATLGVAEF FEFVLKNPHN TQHTVTVEID NPELSVIVDS 

      1030       1040       1050       1060       1070       1080 
QEWRDFKGAA GLHTPVEEDM FHLRGSLAPQ LYLRPHETAH VPFKFQSFSA GQLAMVQASP 

      1090       1100       1110       1120       1130       1140 
GLSNEKGMDA VSPWKSSAVP TKHAKVLFRA SGGKPIAVLC LTVELQPHVV DQVFRFYHPE 

      1150       1160       1170       1180       1190       1200 
LSFLKKAIRL PPWHTFPGAP VGMLGEDPPV HVRCSDPNVI CETQNVGPGE PRDIFLKVAS 

      1210       1220       1230       1240       1250       1260 
GPSPEIKDFF VIIYSDRWLA TPTQTWQVYL HSLQRVDVSC VAGQLTRLSL VLRGTQTVRK 

      1270       1280       1290       1300       1310       1320 
VRAFTSHPQE LKTDPKGVFV LPPRGVQDLH VGVRPLRAGS RFVHLNLVDV DCHQLVASWL 

      1330       1340       1350       1360       1370       1380 
VCLCCRQPLI SKAFEIMLAA GEGKGVNKRI TYTNPYPSRR TFHLHSDHPE LLRFREDSFQ 

      1390       1400       1410       1420 
VGGGETYTIG LQFAPSQRVG EEEILIYIND HEDKNEEAFC VKVIYQ 

« Hide

References

« Hide 'large scale' references
[1]"The gene mutated in juvenile nephronophthisis type 4 encodes a novel protein that interacts with nephrocystin."
Mollet G., Salomon R., Gribouval O., Silbermann F., Bacq D., Landthaler G., Milford D., Nayir A., Rizzoni G., Antignac C., Saunier S.
Nat. Genet. 32:300-305(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT NPHP4 SER-991, INVOLVEMENT IN SLSN4, TISSUE SPECIFICITY, INTERACTION WITH NPHP1.
[2]Erratum
Mollet G., Salomon R., Gribouval O., Silbermann F., Bacq D., Landthaler G., Milford D., Nayir A., Rizzoni G., Antignac C., Saunier S.
Nat. Genet. 32:459-459(2002)
[3]"A gene mutated in nephronophthisis and retinitis pigmentosa encodes a novel protein, nephroretinin, conserved in evolution."
Otto E., Hoefele J., Ruf R., Mueller A.M., Hiller K.S., Wolf M.T.F., Schuermann M.J., Becker A., Birkenhaeger R., Sudbrack R., Hennies H.C., Nuernberg P., Hildebrandt F.
Am. J. Hum. Genet. 71:1161-1167(2002) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANT NPHP4 ARG-754, VARIANT TRP-848.
Tissue: Kidney.
[4]"Prediction of the coding sequences of unidentified human genes. X. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro."
Ishikawa K., Nagase T., Suyama M., Miyajima N., Tanaka A., Kotani H., Nomura N., Ohara O.
DNA Res. 5:169-176(1998) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 212-1426.
Tissue: Brain.
[5]"Mutations in the gene encoding the basal body protein RPGRIP1L, a nephrocystin-4 interactor, cause Joubert syndrome."
Arts H.H., Doherty D., van Beersum S.E.C., Parisi M.A., Letteboer S.J.F., Gorden N.T., Peters T.A., Maerker T., Voesenek K., Kartono A., Ozyurek H., Farin F.M., Kroes H.Y., Wolfrum U., Brunner H.G., Cremers F.P.M., Glass I.A., Knoers N.V.A.M., Roepman R.
Nat. Genet. 39:882-888(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH RPGRIP1L, SUBCELLULAR LOCATION, CHARACTERIZATION OF VARIANT NPHP4 ARG-754, CHARACTERIZATION OF VARIANTS HIS-740 AND TRP-848.
[6]"Mapping the NPHP-JBTS-MKS protein network reveals ciliopathy disease genes and pathways."
Sang L., Miller J.J., Corbit K.C., Giles R.H., Brauer M.J., Otto E.A., Baye L.M., Wen X., Scales S.J., Kwong M., Huntzicker E.G., Sfakianos M.K., Sandoval W., Bazan J.F., Kulkarni P., Garcia-Gonzalo F.R., Seol A.D., O'Toole J.F. expand/collapse author list , Held S., Reutter H.M., Lane W.S., Rafiq M.A., Noor A., Ansar M., Devi A.R., Sheffield V.C., Slusarski D.C., Vincent J.B., Doherty D.A., Hildebrandt F., Reiter J.F., Jackson P.K.
Cell 145:513-528(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: SUBCELLULAR LOCATION, SUBUNIT, INTERACTION WITH NPHP1; RPGRIP1L AND IQCB1.
[7]"Evidence for RPGRIP1 gene as risk factor for primary open angle glaucoma."
Fernandez-Martinez L., Letteboer S., Mardin C.Y., Weisschuh N., Gramer E., Weber B.H., Rautenstrauss B., Ferreira P.A., Kruse F.E., Reis A., Roepman R., Pasutto F.
Eur. J. Hum. Genet. 19:445-451(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH RPGRIP1.
[8]"TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum."
Davis E.E., Zhang Q., Liu Q., Diplas B.H., Davey L.M., Hartley J., Stoetzel C., Szymanska K., Ramaswami G., Logan C.V., Muzny D.M., Young A.C., Wheeler D.A., Cruz P., Morgan M., Lewis L.R., Cherukuri P., Maskeri B. expand/collapse author list , Hansen N.F., Mullikin J.C., Blakesley R.W., Bouffard G.G., Gyapay G., Rieger S., Tonshoff B., Kern I., Soliman N.A., Neuhaus T.J., Swoboda K.J., Kayserili H., Gallagher T.E., Lewis R.A., Bergmann C., Otto E.A., Saunier S., Scambler P.J., Beales P.L., Gleeson J.G., Maher E.R., Attie-Bitach T., Dollfus H., Johnson C.A., Green E.D., Gibbs R.A., Hildebrandt F., Pierce E.A., Katsanis N.
Nat. Genet. 43:189-196(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: INVOLVEMENT IN CILIOPATHIES, VARIANT LEU-160.
[9]"Exome capture reveals ZNF423 and CEP164 mutations, linking renal ciliopathies to DNA damage response signaling."
Chaki M., Airik R., Ghosh A.K., Giles R.H., Chen R., Slaats G.G., Wang H., Hurd T.W., Zhou W., Cluckey A., Gee H.Y., Ramaswami G., Hong C.J., Hamilton B.A., Cervenka I., Ganji R.S., Bryja V., Arts H.H. expand/collapse author list , van Reeuwijk J., Oud M.M., Letteboer S.J., Roepman R., Husson H., Ibraghimov-Beskrovnaya O., Yasunaga T., Walz G., Eley L., Sayer J.A., Schermer B., Liebau M.C., Benzing T., Le Corre S., Drummond I., Janssen S., Allen S.J., Natarajan S., O'Toole J.F., Attanasio M., Saunier S., Antignac C., Koenekoop R.K., Ren H., Lopez I., Nayir A., Stoetzel C., Dollfus H., Massoudi R., Gleeson J.G., Andreoli S.P., Doherty D.G., Lindstrad A., Golzio C., Katsanis N., Pape L., Abboud E.B., Al-Rajhi A.A., Lewis R.A., Omran H., Lee E.Y., Wang S., Sekiguchi J.M., Saunders R., Johnson C.A., Garner E., Vanselow K., Andersen J.S., Shlomai J., Nurnberg G., Nurnberg P., Levy S., Smogorzewska A., Otto E.A., Hildebrandt F.
Cell 150:533-548(2012) [PubMed] [Europe PMC] [Abstract]
Cited for: INTERACTION WITH CEP164.
[10]"Mutational analysis of the NPHP4 gene in 250 patients with nephronophthisis."
Hoefele J., Sudbrak R., Reinhardt R., Lehrack S., Hennig S., Imm A., Muerb U., Utsch B., Attanasio M., O'Toole J.F., Otto E., Hildebrandt F.
Hum. Mutat. 25:411-411(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS NPHP4 CYS-342; TRP-469; GLY-654; TRP-735; ARG-766; ARG-776; GLN-782; HIS-961; THR-1098; TRP-1192; CYS-1284 AND GLU-1287, VARIANTS SLSN4 TYR-3; LEU-91; MET-627; ALA-946 AND MET-1225, VARIANTS MET-29; GLY-544; LYS-618; HIS-740; ILE-765; TRP-848 AND 940-ALA-GLN-941 DEL.
+Additional computationally mapped references.

Web resources

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AY118228 mRNA. Translation: AAM78558.1.
AF537130 mRNA. Translation: AAN06814.1.
AB014573 mRNA. Translation: BAA31648.1.
PIRT00364.
RefSeqNP_055917.1. NM_015102.3.
UniGeneHs.462348.

3D structure databases

ProteinModelPortalO75161.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid129286. 5 interactions.
IntActO75161. 38 interactions.
STRING9606.ENSP00000367398.

PTM databases

PhosphoSiteO75161.

Proteomic databases

PaxDbO75161.
PRIDEO75161.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000378156; ENSP00000367398; ENSG00000131697.
GeneID261734.
KEGGhsa:261734.
UCSCuc001alq.2. human.

Organism-specific databases

CTD261734.
GeneCardsGC01M005922.
HGNCHGNC:19104. NPHP4.
MIM606966. phenotype.
606996. phenotype.
607215. gene.
neXtProtNX_O75161.
Orphanet93592. Juvenile autosomal recessive medullary cystic kidney disease.
3156. Senior-Loken syndrome.
PharmGKBPA134927048.
HUGESearch...
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG81663.
HOGENOMHOG000049142.
HOVERGENHBG024036.
InParanoidO75161.
KOK16478.
OMAHMVRWAV.
PhylomeDBO75161.
TreeFamTF351573.

Enzyme and pathway databases

ReactomeREACT_111102. Signal Transduction.

Gene expression databases

ArrayExpressO75161.
BgeeO75161.
CleanExHS_NPHP4.
GenevestigatorO75161.

Family and domain databases

ProtoNetSearch...

Other

GeneWikiNPHP4.
GenomeRNAi261734.
NextBio93236.
PROO75161.
SOURCESearch...

Entry information

Entry nameNPHP4_HUMAN
AccessionPrimary (citable) accession number: O75161
Entry history
Integrated into UniProtKB/Swiss-Prot: January 27, 2003
Last sequence update: January 27, 2003
Last modified: April 16, 2014
This is version 105 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Relevant documents

SIMILARITY comments

Index of protein domains and families

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 1

Human chromosome 1: entries, gene names and cross-references to MIM