Molecular Studies in the Skeletal Dysplasias

拟议工作的主要目标是在电子基因鉴定中使用连锁研究， 功能和位置候选软骨基因的表达和突变分析 病因不明的骨软骨发育不良的致病基因。关联研究将使用家庭 通过外展工作和转介到国际骨骼发育不良登记处(核心A)收集的数据。这个 选择要研究的障碍的标准包括他们的频率，可能性 疾病基因的鉴定将揭示一个重要的生物途径的重要组成部分，即 能够使用分子信息来提高诊断特征和遗传的清晰度 表型组内的模式(S)以及与其他组分下的研究的相关性 计划项目。通过这些研究，我们将定义新的骨骼的分子机制 了解骨骼发育不良疾病基因的正常功能。具体目标是 为了确定三个表型组中的基因座和疾病基因： 1.短肋骨多指畸形和胸廓发育不良。这两种围产期致命性疾病是 最常见的致命性骨骼发育不良。它们被归类在一起，分类为 基于共同的表型特征的骨骼发育不良，并被假设为 包括软骨外胚层发育不良在内的一系列疾病。我们将测试假设，即它们是 要么是等位基因，要么是疾病基因是途径的组成部分。 2.隐性成骨不全(Ol)。缺乏CRTAP的基因敲除小鼠在 脯氨酸羟化，导致矿化不足的骨骼，类似于成骨不全。这个 这一目标的目标是与其他项目和核心合作，以确定人类隐性Ol CRTAP基因突变的表型。在排除CRTAP的情况下，其他候选基因座将是 包括位于染色体17q21-22上的一个新发现的基因座。这些互动研究将 促进分子基础以及临床和组织学特征的定义 隐性遗传性成骨不全的新机制。 3.短粒体病。短臂炎是一种短干矮小的体型，具有颈椎病的特征和 椎体边缘不规则。表型在临床和遗传上是不同的， 所描述的显性和隐性形式。这一目标的目的是使用关联研究来定义第一个 并确定该实体的诊断特征和自然病史。身份识别 显性短小的疾病基因将促进对每种形式的诊断特征的澄清 并将有助于确定表型的生物学基础

The principal objectives of the proposed work are to use linkage studies, in silico gene identification, cartilage gene expression and mutation analysis of functional and positional candidates to identify the disease genes in osteochondrodysplasias of unknown etiology. The linkage studies will use families collected by outreach efforts and referral to the International Skeletal Dysplasia Registry (Core A). The disorders to be studied have been selected based on criteria that include their frequency, the likelihood that identification of the disease gene will reveal an essential component of an important biological pathway, the ability to use the molecular information to improve definition of the diagnostic features and inheritance pattern(s) within a phenotypic group and the relevance to studies under the other components of the Program Project. Through these studies, we will define new molecular mechanisms for the skeletal dysplasias and understand the normal functions of skeletal dysplasia disease genes. The Specific Aims are to identify the loci and disease genes in three phenotypic groups: 1. Short rib polydactyly and asphxiatinq thoracic dysplasia. These two perinatal lethal disorders are among the most frequent lethal skeletal dysplasias. They have been grouped together in the classification of skeletal dysplasias based on shared phenotypic features and have been hypothesized to be part of a spectrum of disease that includes chondroectodermal dysplasia. We will test the hypothesis that they are either allelic or that the disease genes are components of a pathway. 2. Recessive osteogenesis imperfecta (Ol). Knockout mice with deficiency of Crtap have a defect in prolyl hydroxylation that leads to an undermineralized skeleton resembling osteogenesis imperfecta. The goal of this aim is to work in collaboration with the other Projects and Cores to identify human recessive Ol phenotypes with mutations in CRTAP. In cases where CRTAP is excluded, additional candidate loci will be considered, including a newly identified locus on chromosome 17q21-22. These interactive studies will facilitate the definition of both the molecular basis and the clinical and histological features that characterize novel mechanismsfor recessively inherited osteogenesis imperfecta. 3. Brachyolmia. Brachyolmia is a form of short trunk short stature with a characteristic platyspondyly and irregular margins of the vertebral bodies. The phenotype is clinically and genetically heterogeneous with dominant and recessive forms described. The goal of this aim is to use linkage studies to define the first brachyolmia locus and to determine the diagnostic features and natural history of the entity. Identification of a disease gene for dominant brachyolmia will promote clarification of the diagnostic features of each form and will help define the biological basis of the phenotype