This application is designed to provide George A. Diaz, M.D., Ph.D. with a program of mentored patient-oriented research which will facilitate his development as an independent physician-scientist. Dr. Diaz has completed a residency in pediatrics and, upon completion of his fellowship in human genetics, will become an Assistant Professor of Human Genetics and Pediatrics at the Mount Sinai School of Medicine. During the course of his fellowship, he initiated positional cloning studies of an autosomal recessive skeletal dysplasia, the Kenny-Caffey Syndrome (KCS), using eight consanguineous Kuwaiti pedigrees. The principal manifestations KCS are short stature and hypocalcemia, but significant additional manifestations include eye abnormalities, developmental delay and immune deficits. Although KCS is a rare disease, its unique and protean manifestations suggest that identification of the disease gene will lead to novel insight into bone metabolism and calcium homeostasis as well as into the development of other affected organ systems, including the immune and central nervous systems. During the course of his fellowship, Dr. Diaz undertook a positional cloning project which required that he master linkage analysis and physical mapping. By homozygosity mapping, the KCS gene was successfully localized to chromosome Iq42-43, and the KCS critical region defined by haplotype analysis to an approximately 4 cM interval. To initiate physical mapping of the region, a YAC contig was constructed across the critical region by PcR content mapping using simple tandem repeats and sequence-tagged sites as markers. In order to identify the KCS gene and elucidate its function, further laboratory and clinical investigations are proposed. These studies will accomplish the following: l) the KCS critical region will be narrowed by development of new polymorphic markers and identification of new KCS families; 2) the natural history and phenotypic features of KCS will be further delineated to gain additional insight into the disease pathogenesis and the function of the KCS gene; 3) the physical mapping of the critical region will continue using PAC, BAC or cosmid clones; and 4) candidate genes in the KCS critical region will be evaluated, novel transcripts isolated by exon trapping and cDNA selection, and the disease gene will be identified by mutation analysis techniques. Dr. Diaz will be supported in his endeavors with protected research time, access to the General Research Clinical Center and institutional core facilities, and dedicated laboratory space. His development will be fostered by the serious commitment of his mentors to guide him in the proposed studies and in the responsible conduct of research, and by the outstanding research and intellectual environment at Mount Sinai.
