The gene mutated in juvenile nephronophthisis type 4 encodes a novel protein that interacts with nephrocystin

Abstract

Nephronophthisis, the most common genetic cause of chronic renal failure in children, is a progressive tubulo-interstitial kidney disorder that is inherited as an autosomal recessive trait. The disease is characterized by polyuria, growth retardation and deterioration of renal function during childhood or adolescence. 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. Nephronophthisis can also be associated with conditions affecting extrarenal organs, such as retinitis pigmentosa (Senior-Løken syndrome) and ocular motor apraxia (Cogan syndrome). Three loci are associated with the juvenile, infantile and adolescent forms, on chromosomes 2q13 (NPHP1; refs 5,6), 9q22 (NPHP2; ref. 7) and 3q21 (NPHP3; ref. 8), respectively. NPHP1, the only gene identified so far, encodes nephrocystin, which contains a Src homology 3 (SH3) domain and interacts with intracytoplasmic proteins involved in cell adhesion. Recently, a second locus associated with the juvenile form of the disease, NPHP4, was mapped to chromosome 1p36 (ref. 14). We carried out haplotype analysis of families affected with nephronophthisis that were not linked to the NPHP1, NPHP2 or NPHP3 loci, using markers covering this region. This allowed us to reduce the NPHP4 interval to a one centimorgan interval between D1S2795 and D1S2870, which contains six genes. We identified five different mutations in one of these genes, designated NPHP4, in unrelated individuals with nephronophthisis. The NPHP4 gene encodes a 1,250-amino acid protein of unknown function that we named nephrocystin-4. We demonstrated the interaction of nephrocystin-4 with nephrocystin suggesting that these two proteins participate in a common signaling pathway.

Mutations in INVS encoding inversin cause nephronophthisis type 2, linking renal cystic disease to the function of primary cilia and left-right axis determination

“…We show that recessive mutations in INVS cause NPHP2 in humans and that there is molecular interaction between the NPHP2 product inversin and the NPHP1 product nephrocystin, which is also known to interact with the NPHP4 product nephrocystin-4 (ref. 7) and with the NPHP3 product nephrocystin-3 (ref. 27).…”

“…Similarly, nephrocystin has been described as a novel docking protein [10][11][12][13] that interacts with components of cell-cell and cell-matrix signaling, such as focal adhesion kinase 2, tensin, p130Cas, filamin and nephrocystin-4 or nephroretinin 7 . These observations suggest that proteins associated with renal cystic disease may have multiple functions depending on their localization in different cell compartments and their association with distinct protein assemblies.…”

“…It encodes a novel docking protein, nephrocystin [10][11][12][13] , that interacts with components of cell-cell and cell-matrix signaling, such as focal adhesion kinase 2, tensin, p130Cas and filamin, and with nephrocystin-4 or nephroretinin, the product of NPHP4, mutations in which cause NPHP4 (OMIM 606966; refs. 6,7). Identification of the genes NPHP1 and NPHP4, which are conserved in evolution including in the nematode Caenorhabditis elegans, offered new insights into mechanisms of cell-cell and cell-matrix signaling 6,14 .…”

“…Causative mutations in two genes (NPHP1 and NPHP4) have been identified by positional cloning [4][5][6][7] . There is considerable interest in identifying genes associated with NPHP because its most prominent feature is development of renal interstitial fibrosis 8 , which in chronic renal disease of all origin represents the pathogenic event correlated most strongly to loss of renal function 9 .…”

Expansion of phenotype and genotypic data in CRB2-related syndrome

“…This gene has been linked to nephronophthisis and cerebello-oculo-renal syndrome. 34,35 This finding, together with the BBS7 and BBS12 sequence variants reported in other CRB2-related syndrome patients, indicates that oligogenic inheritance or genetic burden may be critical for the phenotypic expression of CRB2 variants and compromise phenotype. However, further studies to determine the effects of loss of function of these alleles in combination with CRB2 loss of function are needed for verification.…”