MOLECULAR BASIS OF AN X-LINKED INHERITED ARTHROPATHY

骨关节炎是一种慢性衰弱性疾病，影响多达1/3的成年人口。 越来越多的证据表明，遗传因素影响其发展，更好地了解遗传性软骨发育不良无疑将揭示所有退行性关节疾病的共同过程。 迟发性脊椎骨骺发育不良（SEDT）是一种软骨发育不良，其特征是不成比例的身材矮小，X连锁遗传和退行性骨关节炎。该项目的目标是1）定位和分离SEDT基因，2）鉴定导致这种疾病的分子改变，3）深入了解基因产物的生物学功能。 我们已经研究了三个SEDT家庭，包括一个大的谱系，其中包括16个生活受影响的男性和至少20个载体女性。 DNA连锁分析表明，在这些家庭中的SEDT表型与染色体Xp 22上的多态性标记共分离，该区域先前被定义为窝藏SEDT疾病基因。 为了减少候选区域的大小，我们将在我们的家庭内扩大样本量，确定更多的家庭，并通过物理方法验证基因座顺序。 我们将确定候选基因都映射到该地区，并在软骨中转录表达序列标签位点（EST）和cDNA选择技术。 候选基因将根据其与已知基因的同源性优先进行突变分析。将通过SSCP和受影响个体基因组DNA和/或cDNA的直接DNA序列分析来分析主要候选物的突变。 这项研究将通过加强遗传咨询和促进风险个体的早期明确诊断，从而改善他们的临床护理，直接使SEDT家庭受益。 SEDT基因的表达模式和功能可能为设计受影响个体的治疗方式提供线索。 此外，我们预计SEDT的分子描绘将对我们理解负责维持软骨完整性的基本机制以及那些导致骨关节炎软骨退化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.