Missense Mutations in the Rod Domain of the Lamin A/C Gene as Causes of Dilated Cardiomyopathy and Conduction-System Disease

作者：Diane Fatkin, Calum A. MacRae, Takeshi Sasaki, Matthew R. Wolff, Maurizio Porcu, Michael Paul Frenneaux, John James Atherton, Humberto J. Vidaillet Jr., Serena Spudich, Umberto De Girolami, Jonathan G. Seidman, Francesco Muntoni, Gerry Müehle, Wendy Johnson, Barbara A. McDonough, Christine E. Seidman · 发表于：New England Journal of Medicine · 年份：1999 · DOI：10.1056/nejm199912023412302 · 被引用次数：1371 · 研究领域：Nuclear Structure and Function、Skin and Cellular Biology Research、Cardiomyopathy and Myosin Studies

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 ...