ISOLATION OF THE PSEUDOACHONDROPLASIA DISEASE GENE

假性软骨发育不全是一种显性遗传性软骨发育不良 特征为四肢短小，关节松弛，蹒跚步态， 发病性骨关节病。 诊断性放射学异常 骨骺和干骺端，以及内部独特的包涵体 软骨细胞决定了病情 的主要目标 建议的工作是了解分子基础的 假性软骨发育不全，通过分离疾病基因， 确定基因产物的生物学功能。 我们最近 确定假性软骨发育不全表型与 在19号染色体着丝粒周围区域的多态性标记。 一 多发性骨骺发育不良的一种形式最近也被映射到 相同的染色体区域。 我们建议利用最近的数据， 实现以下目标：（A）分离缺陷基因 假性软骨发育不全 我们将完善基因间隔， 该疾病基因，分离包含该区域的分子克隆， 鉴定候选基因，并表征疾病基因。 我们将 测试感兴趣的基因编码细胞外蛋白质的假设， 以软骨特异性方式表达的基质蛋白。 (B)到 确定是否存在遗传异质性， 假性软骨发育不全/多发性骨骺发育不良疾病谱。 我们 将利用19号染色体标记进行连锁研究， 确定其他家族中的疾病基因是否与 同一地区。 (C)确定疾病的染色体位置 在一个家族中的基因与假性软骨发育不全区域无关， 19号染色体。 使用单个大家族和候选基因， 全基因组标记，我们将确定该组中的第二个位点 软骨发育不良 这项工作将直接使假性软骨发育不全的家庭受益， 多发性骨骺发育不良提供更早和更具体的 诊断，从而改善临床护理。 的具体特点 该基因的表达和功能也可能提示合理的 治疗方法。 此外，由于19号染色体的区域 与假性软骨发育不全相关的基因不编码任何已知的 软骨，拟议的研究代表了机会，以确定一个 新的基因产物，并确定分子基础， 骨关节病，结果从它的缺陷，开辟了一个广泛的 生物学和生物化学研究的新领域。

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.