家族性心肌病變之突變基因分析

Abstract

家族性心肌肥厚症是一個具高度外顯率之體染色體顯性遺傳疾病，其臨床表徵差異性大，病人可能毫無症狀或突然發生猝死，目前已發現在肌小節上約11個基因與心肌肥厚症有關，突變型態多達上百種，其中肌凝結合蛋白C（Myosin binding protein C，MYBPC3）是常見的突變點位之一，因此本研究的目的為找出兩個家族性心肌肥厚症之MYBPC3之相關基因型與表現型之間的關連性。本研究針對兩個具有家族性心肌肥厚症之家族之MYBPC3基因所有34個外顯子及外顯子與內顯子連接處，進行基因檢測，實驗結果發現目前為止皆未有文獻紀載的兩種新發生之突變型態，第一種突變發現於Family 1，突變點位於MYBPC3 Exon 31第3624個核苷酸上產生單一鹼基缺失，此基因突變造成codon 1236提早形成終止密碼（Premature stop codon），造成Frameshift mutation，共兩位罹病之家族成員於同樣的基因點位發生突變，其他檢測結果為正常者則無相關臨床表徵；另一型式之突變發生於MYBPC3 Exon 32，第3697個核苷酸產生C>T之突變，由於DNA產生突變，使蛋白質由麩醯胺（Glutamine） 突變為終止密碼（Stop codon），屬Nonsense mutation，而所有具MYBPC3突變之病人其心臟超音波檢查結果皆為異常。綜合以上結果，本研究找到兩種在肌小節之肌凝結合蛋白上產生的新基因突變型，一種為Frameshift mutation，另一種為Nonsense mutation，其指標個案皆有典型之心肌肥厚，伴有缺血性中風之併發症，與先前文獻所證實之Sarcomere基因型突變與家族性心肌肥厚症之表現型有高度關聯性。

Familial Hypertrophic Cardiomyopathy (Familial HCM) is a genetic disease with an autosomal dominant pattern of inheritance. Penetrance for cardiomyopathy is extremely high. However, the clinical manifestations are diverse even in the same family. Familial HCM can be caused by mutations in a number of genes. Hundreds of mutations in 11 responsible genes encoding sarcomeric contractile proteins have been identified. Previous studies found that sarcomeric protein plays an important role in Familial HCM. Mutations in the myosin binding protein C (MYBPC3) are a common cause of Familial HCM. The current study was to investigate the correlation of phenotype and genotype in two kindred of Taiwanese Familial HCM patients. Two Taiwanese HCM families were recruited for mutations screening. The 34 consecutive exons and their exon-intron junctions were sequenced. Two novel sequence variant mutations of MYBPC3 were identified. In Family 1, two subjects with mutation c.3624 delC. in exon 31 was identified, which cause a premature stop codon at codon 1236. In Family 2, a nonsense mutation at c.3697 C>T, leads to p.Glu1233Stop was identified at exon 32 of MYBPC3 gene. The affected family members and probands received echocardiography with the result of HCM. In conclusion, two novel mutations, one for framshift and the other for nonsense in MYBPC3 gene were identified in two executive non-related Taiwanese HCM families. The index cases developed the typical hypertrophic cardiomyopathy with an ischemic stroke. The results are in line with the previous findings that sarcomeric gene mutations are responsible for Familial HCM.