MOLECULAR-GENETIC IDENTIFICATION OF FAMILIES WITH JUVENILE NEPHRONOPHTHISIS TYPE-1 - RATE OF PROGRESSION TO RENAL-FAILURE

Familial juvenile nephronophthisis (NPH), an autosomal recessive cysti c disease of the kidney, is the most common genetic cause of end-stage renal disease (ESRD) in the first two decades of life. A gene locus f or nephronophthisis type 1 (NPH1) has been mapped by linkage analysis to chromosome 2q13. We performed a haplotype analysis in 16 NPH famili es with at least two affected patients with the typical history, clini cal signs and histology of NPH using microsatellite markers of the NPH 1 genetic region. By demonstration of a recombinant event marker D2S18 93 was identified as a novel centromeric flanking marker to the NPH1 c ritical genetic region. Absence of Linkage to the NPH1 locus in six NP H families confirmed the existence of at least one additional gene loc us for NPH. Linkage to the NPH1 locus was demonstrated in 10 families. In 8 of these families a homozygous deletion was identified. These da ta permit for the first time the study of the development of renal fai lure in a subset of NPH1 families, which is most likely homogeneous wi th regard to the responsible gene locus. We present a statistical desc ription of serial serum creatinine measurements in NPH1. Analysis of r enal death revealed a median of 13.1 years. Age-dependent quartiles we re generated for serum creatinine. In summary, the new marker provides a diagnostic tool to aid in the diagnosis of NPH, while the progressi on charts offer a standard for an assessment of the rate of progressio n to ESRD for patients with NPH1 to be used in future therapeutic tria ls and for a prediction of the individual course of the disease.