心肌球蛋白重链基因Arg719Gln突变与家族性肥厚型心肌病

Mutations in the gene encoding for cardiac beta-myosin heavy chain in Chinese families with hypertrophic cardiomyopathy

目的 调查中国人家族性肥厚型心肌病 β 肌球蛋白重链 (β MHC)基因突变情况 ,评估中国人肥厚型心肌病临床特点与基因突变的关系。方法 对 5个独立的肥厚型心肌病家系进行 β MHC基因突变扫描 ,通过聚合酶链反应扩增 β MHC基因 3～ 2 7及 40号外显子 ,通过单链构像多态性及测序检测突变 ,采用限制性片断长度多态性分析检测其他家系成员。结果 发现一家系先证者第19号外显子聚合酶链反应产物单链构象多态性异常 ,测序分析表明该患者 β MHC基因第 719密码子位置发生G→A转换 ,使精氨酸 (Arg)变为谷氨酰胺 (Gln)。该患者临床表现胸痛、心悸及反复发作晕厥 ,超声示室间隔轻度不对称肥厚和左房扩大 ,母亲及姐姐皆有相似临床症状且都已于 38岁猝死。此外 ,在其他 4个家系中还发现了位于 β MHC基因上的ACT6 3ACC、TTT2 44TTC多态位点 ,但与疾病无明显相关。结论 β MHC基因Arg719Gln错义突变位于肌球蛋白重链的头杆结合部 ,该部位系肌球蛋白的重要功能区。该突变表型症状重 ,发病早 ,预后差 ,并与心房扩大和心房纤颤相关 ,提示该突变是致肥厚型心肌病的恶性突变。另一方面 ,研究表明同一突变可有不同的临床表现和预后 ,结合其他 4个家系均未发现错义突变的结果 。

Objective To investigate the beta myosin heavy chain (β MHC) gene mutations in Chinese familial hypertrophic cardiomyopathy (HCM) and to assess the effect of β MHC gene mutations on Chinese patients with HCM. Methods Five unrelated Chinese families with HCM were chosen for the study. Exons 3-27 and exon 40 of the β MHC gene were screened with both the polymerase chain reaction single strand conformation polymorphism (PCR SSCP) method and cycle sequencing of the PCR products. Restriction fragment length polymorphism (RFLP) analysis was performed to confirm the missense mutation in exon 19 observed in one family. Results A proband had a G to A transversion in the β MHC gene codon 719,resulting in the arginine being changed to glutamine. The proband presented with symptoms of chest pain, palpitations and frequent incidents of syncope. A two dimensional echocardiogram showed moderate asymmetrical septal hypertrophy with left atrial enlargement.The patient developed atrial fibrillation and was treated with antiarrhythmic medication. The proband′s mother and 1 of her sisters had similar clinical manifestations, and both died suddenly at the age of 38. In addition, 2 silent nucleotide substitutions (ACT63ACC,TTT244TTC) in the cardiac β MHC gene was identified in the other 4 families. These polymorphisms did not co segregate with the disease in the families. Conclusions The missense mutation Arg719Gln lies in the head rod junction domain of the cardiac β MHC gene. It showed a malignant phenotype of severe clinical symptoms, early onset, poor survival prognosis and was also associated with atrial enlargement and atrial fibrillation. Therefore, it is likely to be the disease causing mutation of hypertrophic cardiomyopathy. Our study also indicates that the same mutation may have different clinical manifestations and consequences. On the other hand, of the five families studied, four families did not have missense mutations, supporting genetic heterogeneity of the disease.