Novel lamin A/C mutations in two families with dilated cardiomyopathy and conduction system disease

Background: The LMNA gene, one of 6 autosomal disease genes implicated in f amilial dilated cardiomyopathy, encodes lamins A and C, alternatively splic ed nuclear envelope proteins. Mutations in lamin A/C cause 4 diseases: Emer y-Dreifuss muscular dystrophy, limb girdle muscular dystrophy type 1B, Dunn igan-type familial partial lipodystrophy, and dilated cardiomyopathy. Methods and Results: Two 4-generation white families with autosomal dominan t familial dilated cardiomyopathy and conduction system disease were found to have novel mutations in the rod segment of lamin A/C. In family A a miss ense mutation (nucleotide G607A, amino acid E203K) was identified in 14 adu lt subjects; disease was manifest as progressive conduction disease in the fourth and fifth decades. Death was caused by heart failure. In family B a nonsense mutation (nucleotide C673T, amino acid R225X) was identified in 10 adult subjects; disease was also manifest as progressive conduction diseas e but with earlier onset (third and fourth decades), ventricular dysrhythmi as, left ventricular enlargement, and systolic dysfunction. Death was cause d by heart failure and sudden cardiac death. Skeletal muscle disease was no t observed in either family. Conclusions: Novel rod segment mutations in lamin A/C cause variable conduc tion system disease and dilated cardiomyopathy without skeletal myopathy.