GENETIC DISSECTION OF A BONE DYSPLASIA/CANCER SYNDROME

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This application is designed to provide Dr. John Martignetti a program of mentored laboratory research to facilitate his development as an independent physician-scientist. After completing his pediatric genetics fellowship, he will become an Assistant Professor of Human Genetics and Pediatrics at the Mount Sinai School of Medicine on July 1, 1998. He recently diagnosed a family with a rare inherited skeletal dysplasia/cancer syndrome, hereditary bone dysplasia (HBD) with malignant change , a syndrome characterized by multiple bone infarctions, cortical thickening, pathologic fractures, and a strong predisposition to an uncommon, highly malignant sarcoma. The etiology of HBD is unknown. Although rare, HBD is of particular interest because its gene defect not only results in abnormal bone formation, but also may cause sporadic sarcomas. Thus, the proposed research is directed to identify the HBD gene and to define its role in normal bone metabolism and in the pathogenesis of HBD and sarcoma. Dr. Martignetti recently initiated studies to identify the disease- causing gene which requires that he master the approaches and techniques of positional cloning. During his fellowship, he obtained DNA samples from three large HBD kindreds and performed a genome-wide search using microsatellite markers. The HBD locus was mapped to a 3 cM region at chromosome 9p21-22, a region previously implicated in the formation of a variety of tumors. To facilitate the isolation of the HBD gene: 1) the HBD linked region will be narrowed by identifying new family members and kindreds and analyzing the recombinants with additional markers; 2) a physical map of the region will be assembled using YAC, P1 and/or BAC clones; 3) candidate genes and ESTs mapping within the HBD region as defined by the physical map will be localized and evaluated; 4) the HBD gene will be identified using exon trapping, LOH analysis, and mutation analysis techniques; 5) the function of the HBD gene will be characterized to determine its function in normal bone metabolism and physiology and its role in causing HBD and tumorigenesis; and 6) the natural history, clinical variability and spectrum of manifestations of HBD will be delineated to gain additional insights into the disease, its pathogenesis, and the function of the HBD gene. Dr. Martignetti's development will be supported with protected research time, dedicated laboratory space, and Departmental and Institutional core facilities. He will be guided in the responsible conduct of research, and his development into an independent researcher will be enhanced by the serious involvement and commitment of his mentors and by the superb research and intellectual environment at Mount Sinai.