A NOVEL GENE THAT ENCODES A PROTEIN WITH A PUTATIVE SRC HOMOLOGY-3 DOMAIN IS A CANDIDATE GENE FOR FAMILIAL JUVENILE NEPHRONOPHTHISIS

Familial juvenile nephronophthisis (NPH) is an autosomal recessive, ge netically heterogeneous disorder, representing the most frequent inher ited cause of chronic renal failure in children, One of the responsibl e loci, NPH1, has been mapped to 2q13, The presence of large homozygou s deletions of similar to 250 kb in the majority of affected patients allowed us to define a minimal deletion interval for NPH1, A BAC conti g covering this interval was established, Combination of large scale g enomic sequencing, cDNA selection and computer-aided analysis led to t he characterization of two transcriptional units, One encodes the alre ady known BENE protein, and the other encodes a novel protein of at le ast 732 amino acids containing a putative src homology 3 domain, In tw o patients carrying the large deletion of the NPH1 region on only one allele, two mutations were detected in two independent exons of the no vel gene, One consists of a single base deletion, causing a frameshift , and the other is a G-->A substitution in the consensus 5' splice don or site, Both mutations thus potentially generate null mutants, One of these mutations was found to segregate with the disease in the family , and the second appeared to be a de novo mutation, We therefore concl ude that this novel gene is a strong candidate for NPH.