BIOCHEMICAL AND MOLECULAR BASIS OF THE COMP DISORDERS

COMP 疾病的生化和分子基础

• 批准号: 2841562
• 负责人: DANIEL H COHN
• 金额: $ 30.29万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-01-15 至 2004-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2841562
• 关键词: RNase protection assay; SDS polyacrylamide gel electrophoresis; achondroplasia; bone development disorder; cartilage development; clinical research; extracellular matrix proteins; family genetics; gene expression; gene mutation; genetic polymorphism; genetically modified animals; human genetic material tag; human subject; immunoelectron microscopy; immunoprecipitation; laboratory mouse; linkage mapping; molecular biology; molecular cloning; nucleic acid sequence; polymerase chain reaction; protein biosynthesis; protein structure function; transmission electron microscopy; western blottings

Pseudoachondroplasia is a dominantly inherited chondrodysplasia characterized by short limbs, joint laxity, a waddling gait, and early onset osteoarthropathy. Diagnostic radiographic abnormalities of the epiphyses and metaphyses, as well as unique inclusion bodies within chondrocytes define the condition. The principal objective of the proposed work is to understand the molecular basis of pseudoachondroplasia and, through the isolation of the disease gene, determine the biological function of the gene product. We have recently determined that the pseudoachondroplasia phenotype is linked to polymorphic markers in the pericentromeric region of chromosome 19. A form of multiple epiphyseal dysplasia has also been recently mapped to the same chromosomal region. We propose to use the recent data to achieve the following goals: (A) To isolate the gene that is defective in pseudoachondroplasia. We will refine the genetic interval containing the disease gene, isolate molecular clones comprising the region, identify candidate genes, and characterize the disease gene. We will test the hypothesis that the gene of interest encodes an extracellular matrix protein that is expressed in a cartilage-specific manner. (B) To determine if there is genetic heterogeneity within the pseudoachondroplasia/multiple epiphyseal dysplasia disease spectrum. We will carry out linkage studies using the chromosome 19 markers to determine if the disease gene in additional families is linked to the same region. (C) To determine the chromosomal location of the disease gene in a family unlinked to the pseudoachondroplasia region of chromosome 19. Using a single, large family and both candidate gene and genome wide markers, we will identify a second locus within this group of chondrodysplasias. This work will directly benefit families with pseudoachondroplasia and multiple epiphyseal dysplasia in providing earlier and more specific diagnosis, and thereby improved clinical care. The specific features of the expression and function of the gene may also suggest rational approaches to therapy. In addition, because the region of chromosome 19 linked to pseudoachondroplasia does not encode any known components of cartilage, the proposed studies represent the opportunity to define a novel gene product from this tissue and identify the molecular basis of the osteoarthropathy that results from defects in it, opening up a broad new area of biological and biochemical investigation.

假牙本质质质是一种主要遗传的软骨增生 特征是四肢短，关节松弛，涉水步态和早期的特征 发作骨关节炎。 诊断X线射线照相异常 Epiphyses和Chandyses，以及独特的包含体 软骨细胞定义条件。 的主要目标 建议的工作是了解 假骨质浮肿，并通过分离疾病基因的分离 确定基因产物的生物学功能。 我们最近有 确定假核糖表型表型与 染色体19的周围质粒区域的多态性标记。 最近还将多个表皮发育不良的形式映射到 相同的染色体区域。 我们建议将最新数据用于 实现以下目标：（a）隔离有缺陷的基因 在假核糖。 我们将完善包含的遗传间隔 疾病基因，包括该区域的分离分子克隆， 鉴定候选基因，并表征疾病基因。 我们将 检验感兴趣基因编码细胞外的假设 以软骨特异性表达的基质蛋白。 （b）到 确定在 假核糖/多发性发育异常疾病谱系。 我们 将使用染色体19标记进行连锁研究 确定其他家庭中的疾病基因是否与 同一区域。 （c）确定疾病的染色体位置 在一个家庭中，基因未链接到伪刺激区域 染色体19。使用一个大家庭和候选基因和 基因组宽标记，我们将在该组中确定第二个基因座 软骨浮肿。 这项工作将直接使患有假核糖核体和的家庭受益 提供早期和更具体的多个另一个骨骼发育不良 诊断，从而改善了临床护理。 的特定特征的特征 基因的表达和功能也可能表明有理 治疗方法。 另外，因为染色体19 链接到假核糖核体不会编码任何已知的组件 软骨，拟议的研究代表了定义A的机会 来自该组织的新基因产物，并确定 由于缺陷而导致的骨关节炎 生物学和生化研究的新领域。