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 y oung adults. We recently identified by positional cloning the causative gen e, NPHP1. Its gene product nephrocystin may play a role in focal adhesion a nd adherens junction signalling. Approximately 80% of all patients with NPH 1 carry large homozygous deletions, which contain the NPHP1 gene. These com mon 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 breakpoi nts 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 homolog ous recombination. We molecularly characterized the centromeric and telomer ic deletion breakpoints by extensive genomic sequencing, Southern blot anal ysis, and cloning and sequencing of the junction fragment. We were able to exactly localize the breakpoints at the position of two guanines. The centr omeric breakpoint was positioned within intron 2 of the NPHP1 gene 360 bp d ownstream of the 5' end of a complete LINE-1 element. Multiple topoisomeras e I and II consensus sequences were found at the breakpoint sites, suggesti ng the involvement of topoisomerase II in the deletion mechanism. These fin dings 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 r ecombination and thereby distinct from the known common deletions. Hum Muta t 16:211-223, 2000. (C) 2000 Wiley-Liss, Inc.