Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease.
Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease.
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DOI：
10.1056/nejm199912023412302
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发表时间：
1999-12-02
影响因子：
158.5
通讯作者：
McDonough, B
中科院分区：
文献类型：
--
作者：
Fatkin, D;MacRae, C;McDonough, B
背景资料：遗传突变导致大约35%的扩张型心肌病病例;然而，与这种疾病相关的基因很少被发现。在此之前，我们定位了一个基因缺陷，负责常染色体显性扩张型心肌病和传导系统疾病的染色体1 p1-q21，其中核被膜蛋白核纤层蛋白A和核纤层蛋白C的LMNA（核纤层蛋白A/C）基因编码。该基因的头部或尾部结构域的突变导致埃默里-德赖富斯肌营养不良症，儿童发病的疾病，其特征是关节挛缩，在某些情况下，由异常的心脏传导在adult.Methods：我们评估了11个常染色体显性扩张型心肌病和传导系统疾病的家庭。核纤层蛋白A/C外显子的序列，确定从每个家庭的先证者，并通过限制性酶消化的变体进行了确认。结果：发现5个新的错义突变，其中4个位于核纤层蛋白A/C基因的（α）-螺旋杆结构域，1个位于核纤层蛋白C尾结构域。每一个突变都导致遗传性、进行性传导系统疾病（窦性心动过缓、房室传导阻滞或房性心律失常）和扩张型心肌病。心力衰竭和猝死在这些家庭中经常发生。没有突变的家庭成员有关节挛缩或骨骼肌病变。血清肌酸激酶水平正常的核纤层蛋白杆突变的家庭成员，但在一些家庭成员的核纤层蛋白C的尾部结构域的缺陷轻度升高。结论：核被膜蛋白A和核纤层蛋白C的不同领域的遗传缺陷选择性地导致扩张型心肌病与传导系统疾病或常染色体显性Emery-Dreifuss肌营养不良症。核纤层蛋白A/C基因杆结构域的错义突变为扩张型心肌病提供了遗传原因，并表明这种中间丝蛋白在心脏传导和收缩性中具有重要作用。（N Engl J Med 1999;341：1715-24.）（C）1999年，马萨诸塞州医学会。
Background: Inherited mutations cause approximately 35 percent of cases of dilated cardiomyopathy; however, few genes associated with this disease have been identified. Previously, we located a gene defect that was responsible for autosomal dominant dilated cardiomyopathy and conduction-system disease on chromosome 1p1-q21, where nuclear-envelope proteins lamin A and lamin C are encoded by the LMNA (lamin A/C) gene. Mutations in the head or tail domain of this gene cause Emery-Dreifuss muscular dystrophy, a childhood-onset disease characterized by joint contractures and in some cases by abnormalities of cardiac conduction during adulthood.Methods: We evaluated 11 families with autosomal dominant dilated cardiomyopathy and conduction-system disease. Sequences of the lamin A/C exons were determined in probands from each family, and variants were confirmed by restriction-enzyme digestion. The genotypes of the family members were ascertained.Results: Five novel missense mutations were identified: four in the (alpha)-helical rod domain of the lamin A/C gene, and one in the lamin C tail domain. Each mutation caused heritable, progressive conduction-system disease (sinus bradycardia, atrioventricular conduction block, or atrial arrhythmias) and dilated cardiomyopathy. Heart failure and sudden death occurred frequently within these families. No family members with mutations had either joint contractures or skeletal myopathy. Serum creatine kinase levels were normal in family members with mutations of the lamin rod but mildly elevated in some family members with a defect in the tail domain of lamin C.Conclusions: Genetic defects in distinct domains of the nuclear-envelope proteins lamin A and lamin C selectively cause dilated cardiomyopathy with conduction-system disease or autosomal dominant Emery-Dreifuss muscular dystrophy. Missense mutations in the rod domain of the lamin A/C gene provide a genetic cause for dilated cardiomyopathy and indicate that this intermediate filament protein has an important role in cardiac conduction and contractility. (N Engl J Med 1999;341:1715-24.) (C)1999, Massachusetts Medical Society.