肥厚型心肌病中β肌球蛋白重链基因的突变：关键功能位点决定预后。
Mutations of the beta myosin heavy chain gene in hypertrophic cardiomyopathy: critical functional sites determine prognosis.
作者信息
Woo A, Rakowski H, Liew J C, Zhao M-S, Liew C-C, Parker T G, Zeller M, Wigle E D, Sole M J
机构信息
Division of Cardiology, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada.
出版信息
Heart. 2003 Oct;89(10):1179-85. doi: 10.1136/heart.89.10.1179.
OBJECTIVES
To assess patients with different types of mutations of the beta myosin heavy chain (beta MHC) gene causing hypertrophic cardiomyopathy (HCM) and to determine the prognosis of patients according to the affected functional domain of beta MHC.
DESIGN AND SETTING
Cohort study of subjects referred to an HCM clinic at an academic hospital.
PATIENTS
70 probands from the HCM clinic were screened for mutations of the beta MHC gene and 148 family members of the genotype positive probands were further assessed. The control group for the genetic studies consisted of 106 healthy subjects.
MAIN OUTCOME MEASURES
Direct DNA sequencing was used to screen 70 probands for mutations of the beta MHC gene. Family members underwent genotypic and detailed clinical, ECG, and echocardiographic assessments. The survival of genotype positive subjects was evaluated according to the type of functional domain affected by the missense mutation and according to phenotypic characteristics.
RESULTS
A mutation of the beta MHC gene was detected in 15 of 70 probands (21%). Of 148 family members studied in these 15 families, 74 were identified with a beta MHC defect. Eleven mutations were detected, including four novel mutations: Ala196Thr, Pro211Leu, Val404Leu, and Arg870Cys. Median survival was 66 years (95% confidence interval (CI) 64 to 77 years) in all affected subjects. There was a significant difference in survival between subjects according to the affected functional domain (p = 0.02). Significant independent predictors of decreased survival were the non-conservative (that is, associated with a change in the amino acid charge) missense mutations that affected the actin binding site (hazard ratio 4.4, 95% CI 1.6 to 11.8; p = 0.003) and those that affected the rod portion of beta MHC (hazard ratio 4.8, 95% CI 1.2 to 19.4; p = 0.03). No phenotypic characteristics were associated with decreased survival or cardiovascular morbidity.
CONCLUSIONS
The type of beta MHC functional domain affected by the missense mutation is predictive of overall prognosis in HCM.
目的
评估因β肌球蛋白重链（βMHC）基因突变导致肥厚型心肌病（HCM）的患者，并根据βMHC受影响的功能结构域确定患者的预后。
设计与背景
对一家学术医院HCM门诊的受试者进行队列研究。
患者
对HCM门诊的70名先证者进行βMHC基因突变筛查，并对148名基因型阳性先证者的家庭成员进行进一步评估。基因研究的对照组由106名健康受试者组成。
主要观察指标
采用直接DNA测序法对70名先证者进行βMHC基因突变筛查。家庭成员接受了基因型以及详细的临床、心电图和超声心动图评估。根据错义突变影响的功能结构域类型和表型特征，评估基因型阳性受试者的生存率。
结果
70名先证者中有15名（21%）检测到βMHC基因突变。在这15个家系研究的148名家庭成员中，74名被确定存在βMHC缺陷。检测到11种突变，包括4种新突变：Ala196Thr、Pro211Leu、Val404Leu和Arg870Cys。所有受影响受试者的中位生存期为66岁（95%置信区间（CI）64至77岁）。根据受影响的功能结构域，受试者的生存率存在显著差异（p = 0.02）。生存率降低的显著独立预测因素是影响肌动蛋白结合位点的非保守（即与氨基酸电荷变化相关）错义突变（风险比4.4，95%CI 1.6至11.8；p = 0.003）以及影响βMHC杆状部分的错义突变（风险比4.8，95%CI 1.2至19.4；p = 0.03）。没有表型特征与生存率降低或心血管疾病发病率相关。
结论
错义突变影响的βMHC功能结构域类型可预测HCM的总体预后。
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