KENNY CAFFEY SYNDROME: BONE SCLEROSIS AND HYPOCALCEMIA

此应用程序旨在为乔治·A·迪亚兹医学博士提供一项以患者为导向的指导研究计划，这将有助于他作为一名独立的内科科学家的发展。迪亚兹博士已经完成了儿科实习，在完成人类遗传学研究后，他将成为西奈山医学院的人类遗传学和儿科学助理教授。在他担任研究员期间，他利用8个科威特血缘关系的家系，启动了对常染色体隐性遗传性骨骼发育不良症--肯尼-卡菲综合征(KCS)的位置克隆研究。KCS的主要表现是身材矮小和低钙血症，但显著的其他表现包括眼睛异常、发育迟缓和免疫缺陷。尽管KCS是一种罕见的疾病，但其独特而千变万化的表现表明，对该疾病基因的识别将导致对骨代谢和钙稳态以及其他受影响的器官系统(包括免疫和中枢神经系统)的发育的新见解。在他担任研究员期间，迪亚兹博士进行了一项位置克隆项目，这要求他掌握连锁分析和物理作图。通过纯合定位，成功地将KCS基因定位在染色体Iq42-43上，并通过单倍型分析将KCS临界区定位到大约4 cM的区间。为了启动该区域的物理作图，使用简单串联重复序列和序列标记的位点作为标记，通过聚合酶链式反应内容作图，跨关键区域构建了YAC重叠群。为了鉴定KCS基因并阐明其功能，建议进行进一步的实验室和临床研究。这些研究将完成以下工作：L)将通过开发新的多态标记和鉴定新的KCS家系来缩小KCS关键区的范围；2)将进一步描绘KCS的自然历史和表型特征，以进一步了解KCS的发病机制和KCS基因的功能；3)将继续使用PAC、BAC或粘粒克隆对KCS关键区进行物理定位；以及4)将评估KCS关键区中的候选基因，通过外显子捕获和cDNA选择分离出新的转录本，并将通过突变分析技术鉴定疾病基因。迪亚兹博士的努力将得到支持，他的研究时间受到保护，可以进入普通研究临床中心和机构核心设施，以及专用的实验室空间。他的发展将由他的导师在建议的研究和负责任的研究中指导他的认真承诺以及西奈山杰出的研究和智力环境来促进。

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.