X-LINKED NEPHROLITHIASIS--MOLECULAR AND CLINICAL STUDIES

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DESCRIPTION (Adapted from the Applicant's Abstract): The applicant has recently described a disease characterized by nephrolithiasis, renal proximal tubular dysfunction, nephrocalcinosis, and ultimately renal failure, affecting only males and inherited in an X-linked recessive pattern. Despite extensive physiologic evaluation of these patients, no primary pathogenic abnormality could be identified for this disease, X-linked recessive nephrolithiasis (XRN). Hypercalciuria and low molecular-weight (LMW) proteinuria are common features of this disease, and the latter is also abnormal in nearly all carrier females. Nephrocalcin, a urinary protein that inhibits calcium stone crystallization, is structurally and functionally abnormal in carriers and patients with XRN. Similar families have been reported from Britain, Japan, Canada, and Italy. It is possible that this disease may represent some proportion of the population with idiopathic calcium nephrolithiasis or chronic renal disease. The applicant has localized the gene for XRN to a region spanning approximately three Mb on the short arm of the X-chromosome (Xpll.23), close to the gene for a similar disease in British families ("Dent's disease") which maps to a different locus on Xp11.22. The present proposal aims to define the biochemical basis of XRN through cloning the gene using a positional cloning approach. The goals are to refine the genetic localization more precisely, then to construct a physical map of the region using YACs and P1 clones, and to identify candidate genes and screen them for mutations. The applicant plans to study expression and function of the gene for XRN and, if it is cloned during this period, the gene for Dent's disease as well. The applicant's research group has recently been strengthened with the addition of two individuals, both of whom have had extensive molecular experience directly relevant to the proposed work. As a secondary effort, clinical studies will be pursued in parallel, to study the abnormalities in the nephrocalcin produced in XRN, and to identify additional cases of XRN by screening several large populations of calcium stone-formers for low molecular-weight proteinuria, a sensitive marker for both XRN and Dent's disease. Mutations in the XRN gene will be sought in such additional cases. These clinical studies will be performed in Syracuse and in collaboration with colleagues at the University of Chicago, Northwestern University and the University of Pennsylvania. It is suggested by the applicant that elucidation of the pathophysiology of this disease should contribute to our understanding of both nephrolithiasis and chronic renal failure.