NPHP4

This gene encodes a protein involved in renal tubular development and function. This protein interacts with nephrocystin, and belongs to a multifunctional complex that is localized to actin- and microtubule-based structures. Mutations in this gene are associated with nephronophthisis type 4, a renal disease, and with Senior-Loken syndrome type 4, a combination of nephronophthisis and retinitis pigmentosa. Alternative splicing results in multiple transcript variants.

Full Name

Nephrocystin 4

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 down-regulate 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).

Biological Process

Actin cytoskeleton organization1 PublicationNAS:UniProtKB
Cell-cell adhesion1 PublicationNAS:UniProtKB
Flagellated sperm motilityIEA:Ensembl
Negative regulation of canonical Wnt signaling pathwayManual Assertion Based On ExperimentIDA:UniProtKB
Photoreceptor cell maintenanceIEA:Ensembl
Photoreceptor cell outer segment organizationIEA:Ensembl
Positive regulation of bicellular tight junction assemblyManual Assertion Based On ExperimentIMP:UniProtKB
Protein localization to ciliary transition zoneManual Assertion Based On ExperimentIBA:GO_Central
Retina development in camera-type eyeIEA:Ensembl
Signal transduction1 PublicationNAS:UniProtKB
Visual behavior1 PublicationNAS:UniProtKB

Cellular Location

Cytoplasm, cytoskeleton, cilium basal body
Cytoplasm, cytoskeleton, microtubule organizing center, centrosome
Cell junction, tight junction
Nucleus
In cultured renal cells, it localizes diffusely in the cytoplasm but, as cells approach confluence, it accumulates to basolateral tight junctions (By similarity).
Localizes to the ciliary transition zone (By similarity).
In the retinal photoreceptor cell layer, localizes at the connecting cilium (By similarity).

Involvement in disease

Nephronophthisis 4 (NPHP4):
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.
Senior-Loken syndrome 4 (SLSN4):
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.