O75161 (NPHP4_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Nephrocystin-4

Alternative name(s):
Nephroretinin

Gene names

Name:	NPHP4
Synonyms:	KIAA0673

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	1426 AA.
Sequence status	Complete.
Protein existence	Evidence 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	Cytoplasm › cytoskeleton › cilium basal body. Cytoplasm › cytoskeleton › centrosome. Cell junction › tight 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.

Ontologies

Keywords
Cellular component	Cell junction Cell projection Cilium Cytoplasm Cytoskeleton Tight junction
Coding sequence diversity	Polymorphism
Disease	Ciliopathy Disease mutation Nephronophthisis Senior-Loken syndrome
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	actin cytoskeleton organization Non-traceable author statement PubMed 12006559. Source: UniProtKB cell-cell adhesion Non-traceable author statement PubMed 12006559. Source: UniProtKB hippo signaling cascade Traceable author statement. Source: Reactome retina development in camera-type eye Inferred from electronic annotation. Source: Compara visual behavior Non-traceable author statement Ref.3. Source: UniProtKB
Cellular_component	cell-cell junction Inferred from direct assay Ref.6. Source: UniProtKB centrosome Inferred from direct assay PubMed 21399614. Source: UniProtKB cilium Inferred from electronic annotation. Source: UniProtKB-KW cytosol Traceable author statement. Source: Reactome membrane Inferred by curator PubMed 12006559. Source: UniProtKB microtubule basal body Inferred from electronic annotation. Source: UniProtKB-SubCell tight junction Inferred from electronic annotation. Source: UniProtKB-SubCell
Molecular_function	structural molecule activity Non-traceable author statement PubMed 12006559. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 1426	1426	Nephrocystin-4		PRO_0000159769
Natural variations
	Natural variant	3	1	D → Y in SLSN4. Ref.10		VAR_022526
	Natural variant	29	1	T → M. Ref.10 Corresponds to variant rs12142270 [ dbSNP | Ensembl ].		VAR_022527
	Natural variant	91	1	F → L in SLSN4. Ref.10		VAR_022528
	Natural variant	160	1	R → 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 variant	342	1	R → C in NPHP4. Ref.10		VAR_022529
	Natural variant	469	1	R → W in NPHP4. Ref.10		VAR_022530
	Natural variant	544	1	A → G. Ref.10 Corresponds to variant rs12093500 [ dbSNP | Ensembl ].		VAR_022531
	Natural variant	618	1	E → K. Ref.10 Corresponds to variant rs571655 [ dbSNP | Ensembl ].		VAR_022532
	Natural variant	627	1	T → M in SLSN4. Ref.10		VAR_022533
	Natural variant	654	1	A → G in NPHP4. Ref.10		VAR_022534
	Natural variant	735	1	R → W in NPHP4. Ref.10		VAR_022535
	Natural variant	740	1	R → H Does not affect interaction with RPGRIP1L. Ref.5 Ref.10 Corresponds to variant rs34248917 [ dbSNP | Ensembl ].		VAR_022536
	Natural variant	754	1	G → R in NPHP4; affects interaction with RPGRIP1L. Ref.3 Ref.5		VAR_015214
	Natural variant	765	1	V → I. Ref.10		VAR_022537
	Natural variant	766	1	Q → R in NPHP4; with color blindness. Ref.10		VAR_022538
	Natural variant	776	1	P → R in NPHP4. Ref.10		VAR_022539
	Natural variant	782	1	H → Q in NPHP4. Ref.10		VAR_022540
	Natural variant	848	1	R → W Does not affect interaction with RPGRIP1L. Ref.3 Ref.5 Ref.10 Corresponds to variant rs17472401 [ dbSNP | Ensembl ].		VAR_015215
	Natural variant	939	1	L → Q. Corresponds to variant rs1287637 [ dbSNP | Ensembl ].		VAR_037622
	Natural variant	940 – 941	2	Missing.		VAR_022541
	Natural variant	946	1	T → A in SLSN4. Ref.10		VAR_022542
	Natural variant	959	1	R → Q. Corresponds to variant rs12084067 [ dbSNP | Ensembl ].		VAR_037623
	Natural variant	961	1	R → H in NPHP4. Ref.10		VAR_022543
	Natural variant	991	1	F → S in NPHP4. Ref.1 Corresponds to variant rs28940891 [ dbSNP | Ensembl ].		VAR_015186
	Natural variant	1098	1	A → T in NPHP4. Ref.10 Corresponds to variant rs41280798 [ dbSNP | Ensembl ].		VAR_022544
	Natural variant	1192	1	R → W in NPHP4. Ref.10		VAR_022545
	Natural variant	1225	1	T → M in SLSN4. Ref.10		VAR_022546
	Natural variant	1284	1	R → C in NPHP4. Ref.10		VAR_022547
	Natural variant	1287	1	Q → E in NPHP4; with hearing loss. Ref.10		VAR_022548

Sequences

	Sequence		Length	Mass (Da)
	O75161 [UniParc]. Last modified January 27, 2003. Version 2. Checksum: 8C974278F4EE4505	FASTA	1,426	157,598
	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

References

	« Hide 'large scale' referencesShow '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. , 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. , 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. , 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

GeneReviews

Cross-references

Sequence databases
EMBL GenBank DDBJ	AY118228 mRNA. Translation: AAM78558.1. AF537130 mRNA. Translation: AAN06814.1. AB014573 mRNA. Translation: BAA31648.1.
IPI	IPI00176920.
PIR	T00364.
RefSeq	NP_055917.1. NM_015102.3.
UniGene	Hs.462348.
3D structure databases
ProteinModelPortal	O75161.
ModBase	Search...
Protein-protein interaction databases
IntAct	O75161. 38 interactions.
STRING	9606.ENSP00000367398.
PTM databases
PhosphoSite	O75161.
Proteomic databases
PaxDb	O75161.
PRIDE	O75161.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000378156; ENSP00000367398; ENSG00000131697.
GeneID	261734.
KEGG	hsa:261734.
UCSC	uc001alq.2. human.
Organism-specific databases
CTD	261734.
GeneCards	GC01M005922.
HGNC	HGNC:19104. NPHP4.
MIM	606966. phenotype. 606996. phenotype. 607215. gene.
neXtProt	NX_O75161.
Orphanet	655. Autosomal recessive medullary cystic kidney disease. 3156. Senior-Loken syndrome.
PharmGKB	PA134927048.
HUGE	Search...
GenAtlas	Search...
Phylogenomic databases
eggNOG	NOG81663.
HOGENOM	HOG000049142.
HOVERGEN	HBG024036.
InParanoid	O75161.
KO	K16478.
OMA	FQLEYVF.
Enzyme and pathway databases
Reactome	REACT_111102. Signal Transduction.
Gene expression databases
ArrayExpress	O75161.
Bgee	O75161.
CleanEx	HS_NPHP4.
Genevestigator	O75161.
GermOnline	ENSG00000131697. Homo sapiens.
Family and domain databases
ProtoNet	Search...
Other
GenomeRNAi	261734.
NextBio	93236.
SOURCE	Search...

Entry information

Entry name

NPHP4_HUMAN

Accession

Primary (citable) accession number: O75161

Entry history

Integrated into UniProtKB/Swiss-Prot:	January 27, 2003
Last sequence update:	January 27, 2003
Last modified:	May 1, 2013
This is version 97 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.