TYPE II COLLAGEN GENE MUTATIONS IN OSTEOARTHRITIS

骨关节炎（OA）的病因目前尚不清楚。 遗传的， 环境、代谢和生物力学因素已被提出 作为发挥可能的作用。兴趣的遗传作用的病因学 OA已扩大基于临床鉴定的阳性遗传 某些疾病子集的模式，如Heberden节点， 不同种族之间OA患病率的差异， 人群中，HLA-A1 B8和HLA- B8和最近证实的II型胶原基因（COL 2A 1） 突变作为原发性全身性OA的原因，在至少一种形式的 疾病，与脊柱软骨发育不良相关的原发性OA。 的 该突变导致在该基因的第519位的精氨酸被替换。 a1（II）胶原分子转化为半胱氨酸，一种在II型胶原中未发现的氨基酸 胶原蛋白从人类或其他物种研究到目前为止。 进一步研究 在我们的实验室已经证明了在一个额外的A1-519突变， 七个家庭中有两个被调查。 本提案中提出的研究 （1）确定a-519突变的患病率， 泛发性OA的家族聚集性和非相关个体 髋关节/膝关节OA;并确定COL 2A 1基因中的其他突变;以及（2） 研究软骨的体液生化标志物（胶原， 蛋白聚糖）代谢，以评估OA的发病机制， 临床应用 这些研究的结果将使我们能够开发 DNA探针;描述个体对OA的疾病易感性;以及 将各种基因缺陷与不同的表型模式相关联， 疾病严重程度。 软骨生化标志物的评估将 增加我们对OA疾病机制的了解。

The etiology of osteoarthritis (OA), is at present unknown. Genetic, environmental, metabolic and biomechanical factors have been suggested as playing possible roles.Interest in a genetic role for the etiology of OA has expanded based on clinical identification of positive inheritance patterns in certain disease sub-sets such as Heberden's nodes, differences in the prevalence of OA among different races and populations, increased frequency of OA in patients with HLA-A1B8 and HLA- B8 and the recent demonstration of a type-II collagen gene (COL2A1) mutation as a cause of primary generalized OA in at least one form of the disease, primary OA associated with a spinal chondrodysplasia. The mutation resulted in the replacement of arginine at position 519 of the a1(II) collagen molecule to cysteine, an amino acid not found in type-II collagen from humans or other species studied so far. Further studies in our laboratory have demonstrated the a1-519 mutation in an additional two of seven families studied. The studies proposed in this proposal will: (1) determine the prevalence of the a-519 mutation with strong family clustering of generalized OA and in non-related individuals with hip/knee OA; and identify other mutations in the COL2A1 gene; and (2) study body fluid biochemical markers of cartilage (collagen, proteoglycan) metabolism to assess OA etiopathologic mechanisms and clinical utility. The results of these studies will allow us to develop DNA probes; to delineate disease susceptibility of individuals to OA; and to correlate various gene defects with varying phenotypic patterns of disease severity. Assessment of biochemical markers of cartilage will add to our understanding of OA disease mechanisms.