ISOLATION OF THE PSEUDOACHONDROPLASIA DISEASE GENE

假性软骨发育不全是一种主要遗传性软骨发育不良。 以四肢短小、关节松弛、步态蹒跚和早起为特征 出现骨关节病。颈椎的诊断放射学异常 内有独特的包含体。 软骨细胞定义了这种情况。该计划的主要目标 建议的工作是了解 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。我们最近做了 确定假性软骨发育不全表型与 19号染色体着丝粒周围区域的多态标记 多发性骨骺发育不良的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来 实现以下目标：(A)分离有缺陷的基因 假性软骨发育不全。我们将细化包含以下内容的遗传间隔 疾病基因，分离组成该区域的分子克隆， 确定候选基因，并确定疾病基因的特征。我们会 测试感兴趣的基因编码胞外基因的假设 以软骨特有的方式表达的基质蛋白。(B)至 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 确定其他家系中的疾病基因是否与 同样的地区。(C)确定疾病的染色体位置 一个与假性软骨发育不全区无连锁的家系基因 19号染色体。使用一个单一的大家庭和候选基因和 全基因组标记，我们将确定这一组中的第二个基因座 软骨发育不良。 这项工作将直接惠及假性软骨发育不全和 多发性骨盆发育不良在提供早期和更具特异性 诊断，从而改善了临床护理。的具体功能 基因的表达和功能也可能暗示着理性的 治疗方法。此外，因为19号染色体的区域 与假性软骨发育不全相关不编码任何已知的成分 对于软骨，拟议的研究代表着定义一种 从该组织中获得新的基因产物，并鉴定其分子基础 由骨关节缺陷引起的骨关节病，打开了广泛的 生物和生化研究的新领域。

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.