REFINED MAPPING OF A GENE (NPH1) CAUSING FAMILIAL JUVENILE NEPHRONOPHTHISIS AND EVIDENCE FOR GENETIC-HETEROGENEITY

Familial juvenile nephronophthisis (NPH) is an au tosomal recessive pr ogressive tubulo-interstitial kidney disorder, responsible for 6-10% o f end-stage renal failure in children, and is frequently associated wi th Leber amaurosis (termed Senior-Loken syndrome). The biochemical bas is of NPH is unknown. We recently reported linkage of the purely renal form of NPH to three markers on chromosome 2. Our results also sugges ted the existence of genetic heterogeneity between NPH and SLS. To map this NPH gene more precisely, we have now tested the segregation of s ix new microsatellite markers and five additional families. Haplotype analyses show unequivocally that four NPH families are not linked to t he chromosome 2 markers, although there are no clinical or pathologica l features discernible in these families that could separate them from the families linked to the chromosome 2 NPH locus (NPH1). This reveal s genetic heterogeneity in the purely renal form of NPH. In situ hybri dization of YAC clones isolated with two closely linked markers assign ed the NPH1 region to 2q13. Furthermore, based on haplotype analysis a nd specific recombination events, the NPH1 gene has been placed betwee n D2S293/D2S340 and D2S121, a genetic interval of about 5-7 cM. (C) 19 94 Academic Press, Inc.