Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy
Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy
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DOI：
10.1056/nejm199804303381802
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发表时间：
1998-04-30
影响因子：
158.5
通讯作者：
Seidman, CE
中科院分区：
文献类型：
--
作者：
Niimura, H;Bachinski, LL;Seidman, CE
背景心肌肌球蛋白结合蛋白C基因突变约占常见肥厚型心肌病病例的15%。这些基因缺陷的致病突变谱和相关的临床特征尚不清楚。方法对家族性肥厚型心肌病患者进行编码心肌肌球蛋白结合蛋白C的DNA序列测定。在16名先证者中发现了突变，他们有574名家庭成员面临遗传这些缺陷的风险。对家系成员进行基因分型，并对212例心肌肌球蛋白结合蛋白C基因突变的家系成员进行临床分析。4个是错义突变；8个缺陷(插入、缺失和剪接突变)被预测为截断心肌肌球蛋白结合蛋白C。错义突变或截断突变的临床表现与肥厚型心肌病的其他遗传原因相似，但发病年龄显著不同。在心肌肌球蛋白结合蛋白C基因突变的50岁以下成年人中，只有58%(117名患者中有68名)有心肌肥厚；疾病外显性在60岁之前仍然不完全。存活率通常比观察到的由肌节蛋白基因的其他突变引起的肥厚型心肌病患者更好。结论心肌肌球蛋白结合蛋白C基因突变的临床表现往往推迟到中老年。心肌肥厚的延迟表达和良好的临床病程可能阻碍对心肌肌球蛋白结合蛋白C基因突变的遗传性的认识。对于以肥厚型心肌病为特征的家族成员，成人生活中的临床筛查可能是有必要的。(C)1998年，马萨诸塞州医学会。
Background Mutations in the gene for cardiac myosin-binding protein C account for approximately 15 percent of cases of familiar hypertrophic cardiomyopathy. The spectrum of disease-causing mutations and the associated clinical features of these gene defects are unknown.Methods DNA sequences encoding cardiac myosin-binding protein C were determined in unrelated patients with familial hypertrophic cardiomyopathy. Mutations were found in 16 probands, who had 574 family members at risk of inheriting these defects. The genotypes of these family members were determined, and the clinical status of 212 family members with mutations in the gene for cardiac myosin-binding protein C was assessed.Results Twelve novel mutations were identified in probands from 16 families. Four were missense mutations; eight defects (insertions, deletions, and splice mutations) were predicted to truncate cardiac myosin-binding protein C. The clinical expression of either missense or truncation mutations was similar to that observed for other genetic causes of hypertrophic cardiomyopathy, but the age at onset of the disease differed markedly. Only 58 percent of adults under the age of 50 years who had a mutation in the cardiac myosin-binding protein C gene (68 of 117 patients) had cardiac hypertrophy; disease penetrance remained incomplete through the age of 60 years. Survival was generally better than that observed among patients with hypertrophic cardiomyopathy caused by other mutations in the genes for sarcomere proteins. Most deaths due to cardiac causes in these families occurred suddenly.Conclusions The clinical expression of mutations in the gene for cardiac myosin-binding protein C is often delayed until middle age or old age. Delayed expression of cardiac hypertrophy and a favorable clinical course may hinder recognition of the heritable nature of mutations in the cardiac myosin-binding protein C gene. Clinical screening in adult life may be warranted for members of families characterized by hypertrophic cardiomyopathy. (C)1998, Massachusetts Medical Society.