[HTML][HTML] Missense mutations in the rod domain of the lamin A/C gene as causes of dilated cardiomyopathy and conduction-system disease
D Fatkin, C MacRae, T Sasaki, MR Wolff… - … England Journal of …, 1999 - Mass Medical Soc
D Fatkin, C MacRae, T Sasaki, MR Wolff, M Porcu, M Frenneaux, J Atherton, HJ Vidaillet Jr…
New England Journal of Medicine, 1999•Mass Medical SocBackground 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 …
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 …
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 α-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.
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