GENETIC DISSECTION OF A BONE DYSPLASIA/CANCER SYNDROME

此应用程序旨在为John Martgnetti博士提供一个程序 指导实验室研究，以促进他作为一个 独立的医生兼科学家。在完成了他的儿科 遗传学奖学金，他将成为人类的助理教授 遗传学和儿科，在西奈山医学院，7月 1998年1月1日。他最近诊断出一家人患有罕见的遗传性骨骼 遗传性骨发育不良(HBD)/癌症综合征 恶变，一种以多发性骨骼为特征的综合征 梗塞、皮质增厚、病理性骨折和强烈的 易患罕见的高度恶性肉瘤。病因学 HBD的具体情况尚不清楚。虽然很罕见，但HBD特别令人感兴趣，因为 它的基因缺陷不仅导致异常的骨形成，而且还 可能会导致零星肉瘤。因此，建议的研究具有一定的指导意义。 鉴定HBD基因并确定其在正常骨中的作用 代谢与HBD和肉瘤的发病机制有关。 马提格内蒂博士最近发起了识别这种疾病的研究- 致病基因，这要求他掌握方法和技术 位置克隆。在他担任研究员期间，他获得了DNA样本 从三个大型HBD家族中分离出来，并使用 微卫星标记。Hbd基因座定位于3 cM的区域 染色体9p21-22，这一区域以前参与了 各种肿瘤。为了便于HBD基因的分离：1) HBD连锁区域将通过识别新的家庭成员和 用附加标记分析重组子；2)a 该地区的物理地图将使用YAC、P1和/或BAC进行汇编 克隆；3)候选基因和EST在HBD区域内定位为 由物理地图定义的将被本地化和评估；4)HBD 基因将通过外显子捕获、杂合性缺失分析和突变进行鉴定 分析技术；5)HBD基因的功能将 其特征是确定其在正常骨骼代谢中的功能和 生理学及其在引起HBD和肿瘤发生中的作用；以及6) 本病的自然病史、临床变异性和表现谱 HBD将被描绘出来，以获得对这种疾病的更多了解，其 发病机制以及HBD基因的功能。 马提格内蒂博士的发展将得到受保护的研究的支持 时间、专用实验室空间、部门和机构 核心设施。他将在负责任的行为中得到指导 研究，他将发展成为一名独立的研究员 由于他的导师和 西奈山一流的研究和智力环境。

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.