家族性早發型骨關節炎的遺傳診斷與諮詢

Abstract

目標：骨關節炎（Osteoarthritis , OA）是一種在人類當中非常常見的關節疾病，目前，我們發現了二個有家族性早發型骨關節炎的家族，從這兩個家族的圖譜來觀察，會發現他們的遺傳模式，符合孟德爾遺傳定律當中的體染色體顯性遺傳。本論文研究的目的是想藉由探索COL2A1基因是否有突變，來建立台灣家族性早發型骨關節炎的基因診斷及遺傳諮詢平台，若是這個模式能夠成功且準確的檢測出致病基因，以後，對於有類似情形的病患，我們就可以幫他們做基因的檢測，給予適當的醫療介入及遺傳諮詢。 方法：我們收集了兩個有家族性早發型骨關節炎的家族，總共23位家屬萃取其白血球的DNA。將這些受試者的檢體，利用PCR及核酸定序法，來分析COL2A1基因上所有exon區域。 結果：我們在其中的一個家族，檢測出罹患骨關節炎的8 位成員，在COL2A1基因的exon 50全部都有3689G→A transition的情形，另外4未罹患骨關節炎的成員，在COL2A1基因exon 50 的3689G位置上則沒有突變的情形發生。3689G→A這樣的改變會造成胺基酸Gly1170Ser，這個位置是在第二型膠原(Type Ⅱ collagen)的GXY重複區域中。 結論：本研究與國立陽明大學的研究，總共三個家族所發現的突變點，恰巧都是在同一個位置，這可能與「奠基者效應」(Founder effect)有關，可見在台灣的族群當中，有家族性關節問題的家族，有相當的程度是與COL2A1基因的3689G→A有關，因此我們希望以此研究為基礎來建立起家族性早發型骨關節炎與股骨頭缺血性壞死的基因診斷及遺傳諮詢平台，對於有類似情形的病患，我們就可以幫他們做基因的檢測，以及遺傳諮詢，期盼可以藉此來協助罹病家族走出家族魔咒。

Objective: Osteoarthritis (OA) is a very common human joint disease. Currently, we have discovered two families with Familial Early-Onset Osteoarthritis. Looking at the pedigree, one discovers the genetic model conforms to autosomal dominant inheritance of Mendel's Laws of Inheritance. This study aims to build a consultation platform for the genetic diagnosis and inheritance of Taiwan’s Familial Early-Onset Osteoarthritis by investigating whether there is mutation of the COL2A1 gene. If this model can successfully and accurately detect the disease causing gene, patients with similar situation can be given a genetic test and then the appropriate medical intervention and hereditary consultation in the future. Methods: We have collected the DNA of leukocytes from the 23 members of the two families with Familial Early-Onset Osteoarthritis. The specimens of the subjects are then subjected to PCR and DNA sequencing to analyze the exon region of the COL2A1 gene. Result: In one family, 3689G→A transition is present in exon 50 of the COL2A1 gene in all 8 family members tested to have OA. In the other four family members without OA, 3689G mutation does not exist in exon 50 of the COL2A1 gene. This results in codon change of Gly1170Ser. The location is in the GXY repeat region of Type II collagen. Conclusions: The results of this study and the study done by National Yang Ming University found that the mutation in the three families studied occurred in the same region. This may be related to Founder effect. It is evident that in Taiwan, for families with familial arthritis problems, 3689G→A of the COL2A1 gene is involved to a certain degree. Therefore, we wish to use this study as a foundation to build the genetic diagnosis and hereditary consultation platform for Familial Early-Onset Osteoarthritis and avascular necrosis of the femoral head. Patients with similar situations can then undergo genetic testing and hereditary consultation. Thus, we hope families with history of the disease can bid farewell to the family curse.