MOLECULAR BASIS OF AN X LINKED INHERITED ARTHROPATHY

X连锁遗传性关节病的分子基础

• 批准号: 2873834
• 负责人: GEORGE E TILLER
• 金额: $ 10万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-09-30 至 1999-04-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2873834
• 关键词: bone development disorder; chondrodystrophy; clinical research; congenital skeletal disorder; family genetics; human genetic material tag; human subject; joint disorder; linkage mapping; osteoarthritis; sequence tagged sites; sex linked trait; single strand conformation polymorphism

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.

骨关节炎是一种慢性衰弱性疾病， 的成年人口。越来越多的证据表明遗传因素 影响这种疾病的发展，并更好地了解 遗传性软骨发育不良无疑会揭示 常见于所有退行性关节疾病。脊椎骨骺发育不良 迟发性软骨病（SEDT）是一种软骨发育不良，其特征在于： 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）本地化和隔离 SEDT的基因，2）确定负责的分子改变 对于这种疾病，和3）深入了解生物功能， 基因产物。我们已经确定了一个大的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，SEDT表型在这个家庭和在第二个 较小的亲缘关系与染色体Xp 22上的多态性标记共分离， 该区域先前被定义为携带SEDT疾病基因。减少 候选区域的大小，我们将在我们的范围内扩大样本量。 家庭，确定其他家庭，并验证基因座顺序， 生理学方法我们将确定候选基因，这两个映射到 使用表达序列在软骨中转录区域和 标签位点（ESTs）和cDNA选择技术。候选基因将是 基于它们与已知基因的同源性优先进行突变分析。 将通过SSCP和直接DNA分析灵长类候选动物的突变 来自受影响个体的基因组DNA和/或cDNA的序列分析。 这项研究将通过提高SEDT家庭的 遗传咨询和促进早期明确诊断 有风险的人，从而改善他们的临床护理。的 SEDT基因的表达模式和功能可能为 为受影响的个人设计治疗方式。而且我们 预计SEDT的分子描绘将具有显著的 影响我们对负责 保持软骨完整性，以及那些有助于 骨关节炎的软骨退化。