With these reports, we identify NPHP4 as an appreciable genetic cause for adult-diagnosed nonsyndromic NPHP that should be considered by adult nephrologists.
The diagnosis of nephronophthisis was made by means of mutational analysis of the NPHP4 gene after isolation of a region of homozygosity in affected individuals by using whole-genome single-nucleotide polymorphism analysis.
In addition, we show that RPGRIP1L colocalizes at the basal body and centrosomes with the protein products of both NPHP6 and NPHP4, known genes associated with MKS, CORS and nephronophthisis (a related renal disorder and ciliopathy).
Their interaction is disrupted by either mutations in RPGRIP1, found in patients with LCA, or by mutations in NPHP4, found in patients with nephronophthisis or SLSN.
Loci associated with an infantile type of NPHP on 9q22-q31 (NPHP2), juvenile types of NPHP on chromosomes 2q12-q13 (NPHP1) and 1p36 (NPHP4) and an adolescent type of NPHP on 3q21-q22 (NPHP3) have been mapped.
We here report identification of the gene (NPHP4) causing NPHP type 4, by use of high-resolution haplotype analysis and by demonstration of nine likely loss-of-function mutations in six affected families.