家族性早發性骨關節炎的遺傳診斷與諮詢II

Abstract

骨關節炎是一種常見關節發生退化的病變，好發於手、膝蓋、髖關節以及脊椎等處，發病後會導致行動不便以及疼痛因而嚴重影響生活品質。除了年齡或是物理性傷害之外，遺傳因子的變異也是造成骨關節炎的一個重要因素。根據之前的研究報導指出，軟骨生成及代謝相關的基因若發生突變，往往會提高骨關節炎發生的機率，帶有這些基因變異的家族常常會有早發性骨關節炎的發生。因此，針對這些與骨關節炎相關的基因建立基因診斷的方法，對於預防骨關節炎的發生是非常重要的，尤其是有家族性早發性骨關節炎病史的家族。本實驗室之前的研究中發現，第二型膠原蛋白的基因發生突變(3689G⣷82;A)與家族性早發性骨關節炎之間有著顯著的關係。本次實驗收集一個早發性骨關節炎家族的檢體進行實驗，共十一位家屬，利用不同引子進行聚合酶鏈鎖反應，將檢體裡COL2A1 基因的部分片段放大，再加以定序。比對結果後發現，在exon34、exon37、exon40以及exon53 等處發現有異合子的現象，分別是SNP ID:rs2276454、rs1635553、rs41272029 以及rs2070739。其中exon53 處所發現之SNPrs2070739)G->A 則會造成蛋白質序列上的變化，由甘胺酸(glycine)變成絲胺酸(serine)。然而，exon53處所發現之SNP 雖然會造成蛋白質序列上的改變，但是經過族譜比對之後與家族性骨關節炎並沒有關聯。相關文獻以及資料中提及，此SNP 在華人的族群裡出現比率偏高，約是六比四，而高加索人的族群裡則是一比九的比例。因此，我們認為此SNP 與此次實驗中遺傳性家族性骨關節炎並沒有相關。根據本研究結果顯示，在台灣地區除了之前報導的第二型膠原蛋白基因發生突變會引發早發性骨關節炎外，或許還有其他的基因變異參與其中，未來值得做更進一步的探討。

Osteoarthritis (OA) is a common type of degenerative arthritis, and it usually concerns hands, knees, hips, and spines, leading to the difficulty in movement, pain, and thus poor quality of life. In addition to aging and physical injuries, genetic susceptibility is also considered an important cause of OA. According to previoustudies, mutations in the related genes of cartilage commonly increase the probability of OA. The families with these mutated genes also have a higher incidence of earlynset OA. As a result, it is very important to establish the method for genetic diagnosis of OA-related to prevent its occurrence, especially for those families in high risk. Previously in our laboratory, we found a mutation of type II collagen (3689G⣷82;A) in a family of early onset OA. In this study, eleven subjects belonging to another victim family of early onset OA were investigated for COL2A1 mutation by PCR-sequencing. After comparison, heterozygotes are found in exon34, exon37, exon40, and exon53 (SNP ID:rs2276454, rs1635553, rs41272029, and rs2070739 respectively). Among these heterozygotes, SNP (rs2070739) G->A, which was found in exon53, results in amino acid change from glycine to serine. However, this mutation does not co-segregate with the phenotype of OA. Moreover, this SNP inxon54 is found commonly in Chinese ethnicity (about 4:6). It is concluded that this SNP (rs2070739) has no relation to familial OA in this study. In conclusion, genes other than COL2A1 may be responsible for familial early-onset OA in this specific family.