Elucidating nephrocystin function by targeted disruption of the NPHP1-gene

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Nephronophthisis (NPH), an autosomal-recessive human kidney disease, is the most frequent genetic cause of chronic renal failure in childhood. Histologically, the disease is characterized bydisintegration of renal tubular basement membranes, atrophy of adjacent renal tubular cel1s, tubulo=interstitial fibrosis and cyst formation. We have recently identified the responsible gene (NPHP1)by a positional cloning approach. The NPHP 1 gene product "nephrocystin" contains a src-homology 3 (SH3). A full=length murine NPHP 1 cDNA was isolated and tissue expression was characterized.Ubiquitous but low expression was found at embryonic stages and in an adult tissues except testis where strong expression was confined to germ cells of the first meiotic division and thereafter.Multiple lines of evidence strongly argue that histological changes in NPH are due to a role of nephrocystin in cell-matrix signaling at focal adhesions.Within this project, an animal model for human NPH will be generated by targeted disruption of the mouse NPHP 1 gene. Mice homozygous mutant for a likely nuJ1 allele of NPHP 1 will be phenotypically characterized. Since nephrocistin represents a novel gene product, we expect from these studies the elucidation of novel mechanisms of cell-matrix and cell-cell signaling in developing and adult kidney, and possibly in other organs. Such insights may also shed light on disease mechanisms of other diseases of the "NPH-complex".