We recently reported hypomorphic NPHP3 mutations in children and young adults with isolated nephronophthisis and associated hepatic fibrosis or tapetoretinal degeneration.
Twenty-five percent of nephronophthisis cases are caused by large homozygous deletions of NPHP1, but six genes responsible for nephronophthisis have been identified.
The DNA sequence analysis of the polymerase chain reaction (PCR) detected no mutations in the NPHP2 (INVS) gene in this child, suggesting that new mutant genes might be responsible for the early onset of ESRD in infantile NPHP with features of JBTS.
In addition, NPHP1 deletions identical to those that cause juvenile nephronophthisis have been identified in a subset of patients with a mild form of cerebellar and brainstem anomaly.
Positional cloning of six novel genes (NPHP1 through 6) as mutated in NPHP and functional characterization of their encoded proteins have contributed to the concept of "ciliopathies."
Nephronophthisis (NPHP) is found in 17-27% of these patients, which was designated JS type B. Mutations in four separate genes (AHI1, NPHP1, CEP290/NPHP6, and MKS3) are linked to JS.
Our aim was to examine 119 families with NPHP and absence of homozygous NPHP1 deletions for mutations in NPHP2-6 and the two candidate genes BCL2 and CYS1.
However, because NPHP1 mutations usually cause isolated nephronophthisis, the factors that predispose to the development of neurologic involvement are poorly understood.
First, Inversin, a protein mutated in nephronophthisis type II was found to act as a switch between the canonical and the noncanonical Wnt cascade, suggesting that beta-catenin/TCF-dependent gene transcription has to be curtailed to allow normal tubular differentiation.
A control subject with NPHP and with a homozygous NPHP1 deletion was also identified, retrospectively, as having a mild MTS and borderline intelligence.
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.