A deletion distinct from the classical homologous recombination of juvenile nephronophthisis type 1 (NPH1) allows exact molecular definition of deletion breakpoints.
Juvenile nephronophthisis, an autosomal recessive cystic kidney disease, is the most common genetic cause of end-stage renal disease in children and young adults. We recently identified by positional cloning the causative gene, NPHP1. Its gene product nephrocystin may play a role in focal adhesion and adherens junction signaling. Approximately 80% of all patients with NPH1 carry large homozygous deletions, which contain the NPHP1 gene. These common deletions are positioned within a complex arrangement of large inverted and direct repeats, suggesting unequal recombination as a potential cause for their origin. In this study we have characterized the deletion breakpoints in a family with juvenile nephronophthisis that bears a unique maternal deletion of the NPHP1 gene, which is not the result of an event of homologous recombination. We molecularly characterized the centromeric and telomeric deletion breakpoints by extensive genomic sequencing, Southern blot analysis, and cloning and sequencing of the junction fragment. We were able to exactly localize the breakpoints at the position of two guanines. The centromeric breakpoint was positioned within intron 2 of the NPHP1 gene 360 bp downstream of the 5' end of a complete LINE-1 element. Multiple topoisomerase I and II consensus sequences were found at the breakpoint sites, suggesting the involvement of topoisomerase II in the deletion mechanism. These findings provide the first data on a potential mechanism for a deletion of the NPHP1 gene, that most likely is not the result of an event of homologous recombination and thereby distinct from the known common deletions.