Nephronophthisis 4

A number sign (#) is used with this entry because of evidence that nephronophthisis-4 (NPHP4) is caused by homozygous or compound heterozygous mutation in the NPHP4 gene (607215) on chromosome 1p36.

For a general phenotypic description and a discussion of genetic heterogeneity of nephronophthisis, see NPHP1 (256100).

Clinical Features

Three loci had been mapped for nephronophthisis, the leading genetic cause of chronic renal failure in young adults: juvenile NPHP1 (256100) on 2q13; infantile nephronophthisis (NPHP2; 602088) on 9q22-q31; and adolescent nephronophthisis (NPHP3; 604387) on 3q21-q22. By renal histology the 3 forms of the disease are indistinguishable, all 3 exhibiting a triad of interstitial-cell infiltrates, renal tubular-cell atrophy with cysts arising from the corticomedullary junction of the kidneys, and renal interstitial fibrosis (Waldherr et al., 1982). Clinically, there is a statistically different age at onset at end-stage renal disease: terminal renal failure develops at median ages of 1 year, 13 years, and 19 years, in NPHP2, NPHP1, and NPHP3, respectively (Omran et al., 2000). In the patients studied by Schuermann et al. (2002), who reported the chromosomal localization of a fourth gene locus, NPHP4, end-stage renal disease commenced within a wide age range, 11 to 34 years.

Mapping

Schuermann et al. (2002) reported the chromosomal localization of a fourth locus for nephronophthisis, NPHP4. The 7 families studied by Schuermann et al. (2002) were part of 61 multiplex families with NPHP, ascertained worldwide during the previous 10 years. In 26 of them, NPHP1 was excluded on the basis of either absence of mutations in the NPHP1 gene or lack of linkage to this locus. After exclusion both of families with extrarenal symptoms and of families compatible with linkage to either NPHP2 or NPHP3, 7 multiplex families remained. A total-genome search for linkage was performed in these 7 families. One family was excluded on the basis of mutation in the paracellin-1 gene (PCLN1; 603959), indicating that this family in fact suffered from primary hypomagnesemia with hypercalciuria and nephrocalcinosis (248250). By high-resolution haplotyping in the remaining 6 families, Schuermann et al. (2002) detected a 1p36 interval compatible with linkage in all. In one family 2 markers were found to be homozygous in affected individuals. Homozygosity by descent was established by the finding. On both the paternal and the maternal sides, they identified an ancestor with a rare surname that occurred only 96 times among 40 million entries in the German online telephone registry. The fact that both the paternal and the maternal ancestors came from a small township facilitated the tracing of the postulated consanguinity loop. They identified a common ancestor born in 1677. On the basis of consanguinity by descent, the lod score for this family (F30) alone was 5.8 at recombination fraction zero for marker D1S253. The existence of shorter loops of consanguinity, however, could not be excluded in this kindred.

The association of nephronophthisis with autosomal recessive retinitis pigmentosa identifies the Senior-Loken syndrome (266900). Schuermann et al. (2002) found that a locus for Senior-Loken syndrome maps to the NPHP4 region on 1p36 (see 606996).

Molecular Genetics

To narrow the location of the NPHP4 gene, Mollet et al. (2002) carried out haplotype analysis of families with nephronophthisis that did not show linkage to NPHP1, NPHP2, or NPHP3, using markers covering the 1p36 region. This allowed them localize the NPHP4 gene within a 1-cM interval between D1S2795 and D1S2870, which contained 6 genes. They identified 5 mutations in 1 of these genes, designated NPHP4, in unrelated individuals with nephronophthisis; see 607215.0001-607215.0005.