Molecular Studies in the Skeletal Dysplasias

拟议工作的主要目标是利用连锁研究，在硅片基因鉴定， 软骨基因表达和突变分析的功能和位置的候选人，以确定 病因不明的骨软骨发育不良中的疾病基因。联系研究将使用家庭 通过外展工作收集，并转介到国际骨骼发育不良登记处（核心A）。的 要研究的疾病是根据标准选择的，这些标准包括它们的频率、 疾病基因的鉴定将揭示一个重要生物途径的基本组成部分， 能够使用分子信息来改善诊断特征和遗传的定义 表型组内的模式以及与表型组其他组分下研究的相关性 计划项目。通过这些研究，我们将确定新的分子机制，为骨骼肌 了解骨骼发育不良疾病基因的正常功能。具体目标是 以确定三个表型组中的基因座和疾病基因： 1.短肋多指（趾）畸形和胸廓发育不良。这两种围产期致命疾病是 最常见的致命骨骼发育不良它们被归为一类， 骨骼发育不良的基础上共享的表型特征，并已被假设为一个 包括软骨外胚层发育不良在内的一系列疾病。我们将检验它们是 等位基因或疾病基因是途径的组成部分。 2.隐性成骨细胞（Ol）。缺乏Crtap的基因敲除小鼠在以下方面存在缺陷： 脯氨酰羟基化，导致矿化不足的骨骼，类似于骨生成障碍。的 这个目标的目标是与其他项目和核心合作，以确定人类隐性遗传性骨关节炎 CRTAP突变的表型。在CRTAP被排除的情况下，其他候选基因座将被排除。 考虑，包括染色体17 q21 -22上的一个新发现的基因座。这些互动研究将 有助于定义表征的分子基础以及临床和组织学特征， recklessinherited osteogenesis recklessinherited osteogenesis. 3.短嗅觉症短肢症是一种躯干短小的形式，具有特征性的扁平脊椎， 椎体边缘不规则。表型在临床和遗传上是异质的， 显性和隐性形式描述。这一目标的目的是利用联系研究来确定第一个 brachyolmia基因座，并确定实体的诊断特征和自然史。鉴定 显性短肢症的疾病基因将有助于澄清每种形式的诊断特征， 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