MOLECULAR BASIS OF AN X-LINKED INHERITED ARTHROPATHY

骨关节炎是一种慢性衰弱疾病，影响多达三分之一的成年人。越来越多的证据表明，遗传因素影响其发育，对遗传性软骨发育不良的更好理解无疑将有助于揭示所有退行性关节疾病的共同过程。迟发性脊柱骨骺发育不良(SEDT)是一种以不成比例的矮小、X连锁遗传和退行性骨关节炎为特征的软骨发育不良。这个项目的目标是1)定位和分离SEDT的基因，2)鉴定导致这种疾病的分子变化，3)深入了解基因产物的生物学功能。我们研究了三个SEDT家系，其中包括一个大的家系，其中包括16名在世的受影响男性和至少20名携带者女性。DNA连锁分析表明，这些家系的SEDT表型与染色体Xp22上的多态标记聚集在一起，该区域先前被定义为SEDT病基因的所在地。为了缩小候选区域的大小，我们将扩大我们的家族内的样本大小，确定更多的家族，并通过物理方法验证基因座的顺序。我们将使用表达序列标记位点(ESTs)和基因选择技术来识别既能定位到该区域又能在软骨中转录的候选基因。候选基因将根据它们与已知基因的同源性优先进行突变分析。主要候选者将通过SSCP和来自受影响个人的基因组DNA和/或cDNA的直接DNA序列分析来分析突变。这项研究将通过加强遗传咨询和促进对高危个体的早期明确诊断，从而改善他们的临床护理，直接使SEDT患者家庭受益。SEDT基因的表达模式和功能可能为设计针对受影响个体的治疗方式提供线索。此外，我们预计SEDT的分子描述将对我们理解维持软骨完整性的基本机制以及那些在骨关节炎中导致软骨退变的机制产生重大影响。

Osteoarthritis is a chronic debilitating disease which affects up to 1/3 of the adult population. Growing evidence suggests that genetic factors influence its development, 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 studied three SEDT families, including one large pedigree which includes 16 living affected males and at least 20 carrier females. DNA linkage analysis indicates that the SEDT phenotype in these families cosegregates 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 physical 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. Prime 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.