PATHOGENESIS OF FAMILIAL JUVENILE NEPHRONOPHTHISIS

Vanderbilt University, Nashville TN

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Abstract

The long-term objective of this proposal is to understand the nature of the cellular defects underlying the pathogenesis of familial juvenile nephronophthisis (NPH) -- a common genetic cause of kidney failure in children. Although clinical and histological observations indicate NPH results from a loss of normal excretory tubule function, the pathogenesis of the disease remains obscure. Recently a human gene mutated in the majority of NPH cases was isolated and the sequence of its encoded protein ("nephrocystin") was determined. A clue to the biochemical function of nephrocystin is the presence of a "Src homology 3" (SH3) domain known for mediating specific protein-protein interactions. New insight into the pathogenesis of NPH will now come from further study of nephrocystin. In preliminary studies, cDNAs encoding mouse nephrocystin have been isolated and the transcripts have been detected during post-implantation mouse embryogenesis and in a variety of adult tissues including the kidney. New information concerning the biochemical function of nephrocystin was obtained by identifying a tyrosine kinase substrate, pl30Cas, as a protein bound by the nephrocystin SH3 domain and by showing that nephrocystin localizes to lateral membranes of polarized epithelial cells. These observations led to our general hypothesis that nephrocystin functions in the morphogenesis and/or maintenance of the kidney tubular epithelium, requiring specific interactions with pl30Cas and other proteins involved in cell adhesive interactions. To test and expand the hypothesis, specific aims are proposed to: 1) determine the spatial pattern of expression of nephrocystin in developing mouse embryos and in the adult kidney, 2) further identify and characterize relevant nephrocystin-interacting proteins, and 3) determine the effects of nephrocystin on adhesion regulated p130Cas tyrosine phosphorylation and epithelial cell tight junction formation and tubulogenesis.