Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease.

Background: Inherited mutations cause approximately 35 percent of cases of dilated cardiomyopathy; however, few genes associated with this disease hav e been identified. Previously, we located a gene defect that was responsibl e for autosomal dominant dilated cardiomyopathy and conduction-system disea se 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-on set disease characterized by joint contractures and in some cases by abnorm alities of cardiac conduction during adulthood. Methods: We evaluated 11 families with autosomal dominant dilated cardiomyo pathy and conduction-system disease. Sequences of the lamin A/C exons were determined in probands from each family, and variants were confirmed by res triction-enzyme digestion. The genotypes of the family members were ascerta ined. 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 doma in. 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 frequ ently within these families. No family members with mutations had either jo int contractures or skeletal myopathy. Serum creatine kinase levels were no rmal 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 pr oteins lamin A and lamin C selectively cause dilated cardiomyopathy with co nduction-system disease or autosomal dominant Emery-Dreifuss muscular dystr ophy. Missense mutations in the rod domain of the lamin A/C gene provide a genetic cause for dilated cardiomyopathy and indicate that this intermediat e filament protein has an important role in cardiac conduction and contract ility. (N Engl J Med 1999;341:1715-24.) (C)1999, Massachusetts Medical Soci ety.