A NOVEL GENE ENCODING AN SH3 DOMAIN PROTEIN IS MUTATED IN NEPHRONOPHTHISIS TYPE-1

Juvenile nephronophthisis (NPH), an autosomal recessive cystic kidney disease, is the primary genetic cause of chronic renal failure in chil dren. About two thirds of patients with NPH carry a large homozygous d eletion at the gene locus NPH1 on 2q13. We here identify a novel gene, NPHP1, which extends over most of this common deletion. The 4.5-kb tr anscript encodes a protein with an SH3 domain, which is highly conserv ed throughout evolution. The 11-kb interval between the 3' end of NPHP 1 and an inverted repeat containing the distal deletion breakpoint was found to contain the first exon of a second gene, MALL. In patients w ith a hemizygous deletion of the NPH1 region, additional point mutatio ns were found in NPHP1 but not in MALL.