- 學位論文
兩種單基因遺傳疾病的分子變異分析 ──板素缺乏先天性肌失養症和體顯性艾梅氏肌失養症
The Molecular Analysis of Two Monogenic Diseases: Merosin-Deficient Congenital Muscular Dystrophy & Autosomal Dominant Emery-Dreifuss Muscular Dystrophy
摘要
單基因遺傳疾病即是指由特定單基因的遺傳變異所造成的遺傳疾病，因此這一類的遺傳疾病大多符合所謂的孟德爾遺傳定律（mendelian trait），即其基因突變傳給下ㄧ代的平均機率都呈現出一固定的比例。與其他多基因遺傳的疾病如糖尿病、高血壓相比，相對的單基因遺傳疾病的發生率比較低，且單基因遺傳疾病通常也擁有較明確的遺傳模式和較固定的臨床症狀。 先天性肌失養症(Congenital Muscular Dystrophy)是一群各由不同基因遺傳變異所造成的神經肌肉疾病。在先天性肌失養症中大都屬於單一基因的遺傳疾病。其中板素缺乏先天性肌失養症(Merosin-Deficient Congenital Muscular Dystrophy)，是由於人類LAMA2基因帶有基因突變所造成，而這種疾病是屬於體隱性遺傳。相對的，體顯性艾梅氏肌失養症(Autosomal Dominant Emery-Dreifuss Muscular Dystrophy)，則是由於LMNA基因產生突變所造成。目前在台灣這兩種疾病都已經被發現但基因變異還未被研究，因此本研究想藉由遺傳基因研究技術來找出造成這兩種遺傳疾病的基因變異，以供日後遺傳諮詢及基因研究的參考。 一個六歲板素缺乏先天性肌失養症台灣女童的LAMA2基因分析發現，其中一股DNA中有2098delAG突變造成框構轉移（frameshift），這個改變使得這股DNA轉譯出不完整的蛋白質，是由其母親將帶有2098delAG的LAMA2基因遺傳給病童。而病人LAMA2基因的另一突變，為1352C＞T →R435X造成無意義突變而導致轉譯過程中多肽合成的提前終止。目前為止1352C＞T是一個在LAMA2基因上突變新發現的形式。 分析一個體顯性艾梅氏肌失養症的家庭，發現母親和姐妹三個人的LMNA基因一股DNA正常，另一股DNA帶有T6293G →W520G的錯義突變(missense mutation)。目前在中國人這是首次證明由LMNA基因突變造成體顯性艾梅氏肌失養症的病例，其突變形式T6293G →W520G也是第一次被証明。
並列摘要
Monogenic diseases mean a group of genetic diseases which are caused by single corresponding gene mutation. This kind of diseases are often called mendelian trait because they occur on average in fixed proportion among the offspring of specific type of mating. Comparing with polygenic disease such as diabetes and hypertension, single-gene disorders are relatively less frequent but with clear mode of inheritance and similar onset of disease. Congenital muscular dystrophies (CMD) are a group of heterogeneous, neuromuscular disorders. The merosin-deficient CMD is an monogenic, autosomal recessive disorder and caused by the mutations in the LAMA2 gene. Autosomal dominant Emery-Dreifuss muscular dystrophy results from mutations of the LMNA gene. There were cases of merosin-deficient CMD and autosomal dominant Emery-Dreifuss muscular dystrophy diagnosed in Taiwan in recent years. This is the first report of the mutation analysis of LAMA2 and LMNA genes in Taiwan. In this study, we report one six-year-old girl with merosin-deficient CMD. She has one frameshift mutation（2098delAG）in one copy of the LAMA2 gene, this mutation predicts a truncated protein. A nonsense mutation（1352C＞T）in the other copy of the gene also predicts a truncated protein, and this mutation is a novel form in LAMA2 gene. Then we report one family with autosomal dominant Emery-Dreifuss muscular dystrophy. The mother and her two dauthers have missense mutation （T6293G）in one copy of the LMNA gene, and the mutation is also a novel form in this gene.