MOLECULAR BASIS OF AN X LINKED INHERITED ARTHROPATHY

骨性关节炎是一种慢性衰弱疾病，影响多达1/3。 成年人口的比例。越来越多的证据表明，遗传因素 影响本病的发展，并更好地了解 遗传性软骨发育不良无疑将揭示这一过程 在所有退行性关节疾病中都很常见。脊柱骨盆发育不良 迟发性软骨发育不良(SEDT)是一种软骨发育不良，其特征是 不成比例的矮小、X连锁遗传和退化性 骨性关节炎。该项目的目标是1)本地化和隔离 SEDT的基因，2)识别与之相关的分子改变 对这种疾病的治疗，以及3)洞察其生物学功能 基因产物。我们已经确定了一个庞大的SEDT家族，其中包括 16名受影响的男性和至少20名携带者女性。DNA连锁 分析表明，该家族的SEDT表型 在染色体Xp22上带有多态标记的小亲缘共分离， 先前被定义为含有SEDT疾病基因的区域。减少 候选区域的大小，我们将在我们的 族、确定其他族并按以下方式验证轨迹顺序 生理学方法。我们将确定候选基因，它们都映射到 该区域使用表达序列在软骨中转录 标签位点(EST)和基因选择技术。候选基因将是 根据它们与已知基因的同源性优先进行突变分析。 灵长类候选动物将通过SSCP和直接DNA进行突变分析 来自受影响个体的基因组DNA和/或cDNA的序列分析。 这项研究将直接惠及患有SEDT的家庭 遗传咨询和促进早期明确诊断 因此，改善他们的临床护理。这个 SEDT基因的表达模式和功能可能为研究提供线索 为受影响的个人设计治疗方式。此外，我们 预计SEDT的分子描述将具有重要的 影响我们对负责的基本机制的理解 保持软骨的完整性，以及那些有助于 骨性关节炎的软骨退变。

Osteoarthritis is a chronic debilitating disease which affects up to 1/3 of the adult population. Growing evidence suggests that genetic factors influence the development of this disease, and a better understanding of inherited chondrodysplasias will undoubtedly shed light on the processes common to all degenerative joint disease. Spondyloepiphyseal dysplasia tarda (SEDT) is a chondrodysplasia which is characterized by disproportionate short stature, X-linked inheritance, and degenerative osteoarthritis. The goals of this project are 1) to localize and isolate the gene for SEDT, 2) to identify the molecular alterations responsible for this disease, and 3) to gain insight into the biological function of the gene product. We have ascertained a large SEDT family which includes 16 living affected males and at least 20 carrier females. DNA linkage analysis indicates that the SEDT phenotype in this family and in a second small kindred co-segregates with polymorphic markers on chromosome Xp22, a region previously defined as harboring the SEDT disease gene. To reduce the size of the candidate area, we will expand the sample size within our families, ascertain additional families, and verify locus order by physiological methods. We will identify candidate genes which both map to the region and are transcribed in cartilage using expressed sequence tagged sites (ESTs) and cDNA selection techniques. Candidate genes will be prioritized for mutation analysis based on their homology to known genes. Primate candidates will be analyzed for mutations by SSCP and direct DNA sequence analysis of genomic DNA and/or cDNA from affected individuals. This research will directly benefit families with SEDT by enhancing genetic counseling and facilitating early definitive diagnosis for individuals at risk, therefore improving their clinical care. The expression pattern and function of the SEDT gene may provide clues for designing therapeutic modalities for affected individuals. Moreover, we anticipate that the molecular delineation of SEDT will have a significant impact on our understanding of basic mechanisms responsible for maintaining cartilage integrity, as well as those contributing to cartilage degeneration in osteoarthritis.