NPHP4

Highest pathogenic variant AF is 0.00014005064

Gene type

protein_coding

Transcript type

protein_coding

Transcript

ENST00000378156

Coding exons

29

Length

129663

Individuals with no LoFs

124517

Homozygous LoFs

1

Heterozygous LoFs

193

Defined

124711

p

0.000778

Function

FUNCTION: Involved in the organization of apical junctions; the function is proposed to implicate a NPHP1-4-8 module (PubMed:19755384, PubMed:21565611). Does not seem to be strictly required for ciliogenesis (PubMed:21565611). Required for building functional cilia. Involved in the organization of the subapical actin network in multiciliated epithelial cells. Seems to recruit INT to basal bodies of motile cilia which subsequently interacts with actin-modifying proteins such as DAAM1 (By similarity). In cooperation with INVS may downregulate the canonical Wnt pathway and promote the Wnt-PCP pathway by regulating expression and subcellular location of disheveled proteins. Stabilizes protein levels of JADE1 and promotes its translocation to the nucleus leading to cooperative inhibition of canonical Wnt signaling (PubMed:21498478, PubMed:22654112). Acts as negative regulator of the hippo pathway by association with LATS1 and modifying LATS1- dependent phosphorylation and localization of WWTR1/TAZ (PubMed:21555462). {ECO:0000250|UniProtKB:B0DOB4, ECO:0000250|UniProtKB:P59240, ECO:0000269|PubMed:21498478, ECO:0000269|PubMed:21555462, ECO:0000269|PubMed:21565611, ECO:0000269|PubMed:22654112, ECO:0000305|PubMed:19755384}.;

Disease

DISEASE: Note=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 (PubMed:21258341). {ECO:0000269|PubMed:21258341}.; DISEASE: 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. {ECO:0000269|PubMed:12244321, ECO:0000269|PubMed:15776426, ECO:0000269|PubMed:21546380, ECO:0000269|PubMed:22550138}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=May be involved in male infertility. Homozygosity for a frameshift truncating mutation are associated with markedly abnormal sperm morphology. {ECO:0000269|PubMed:23574405}.; DISEASE: Note=May be involved in cardiac laterality defects and heterotaxy. Homozygosity for a frameshift truncating mutation are associated with markedly abnormal sperm morphology. {ECO:0000305|PubMed:22550138}.;