Mutations in Sarcomere Protein Genes as a Cause of Dilated Cardiomyopathy

doi:10.1056/NEJM200012073432304

Volume 343:1688-1696		December 7, 2000		Number 23

Mutations in Sarcomere Protein Genes as a Cause of Dilated Cardiomyopathy

Mitsuhiro Kamisago, M.D., Sapna D. Sharma, M.D., Steven R. DePalma, Ph.D., Scott Solomon, M.D., Pankaj Sharma, M.D., Ph.D., Barbara McDonough, R.N., Leslie Smoot, M.D., Mary P. Mullen, M.D., Ph.D., Paul K. Woolf, M.D., E. Douglas Wigle, M.D., J.G. Seidman, Ph.D., and Christine E. Seidman, M.D.

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ABSTRACT

Background The molecular basis of idiopathic dilated cardiomyopathy,a primary myocardial disorder that results in reduced contractilefunction, is largely unknown. Some cases of familial dilatedcardiomyopathy are caused by mutations in cardiac cytoskeletalproteins; this finding implicates defects in contractile-forcetransmission as one mechanism underlying this disorder. To elucidatethis important cause of heart failure, we investigated othergenetic causes of dilated cardiomyopathy.

Methods Clinical evaluations were performed in 21 kindreds withfamilial dilated cardiomyopathy. A genome-wide linkage studyprompted a search of the genes encoding ${beta}$ -myosin heavy chain,troponin T, troponin I, and ${alpha}$ -tropomyosin for disease-causingmutations.

Results A genetic locus for mutations associated with dilatedcardiomyopathy was identified at chromosome 14q11.2–13(maximal lod score, 5.11; ${upsilon}$ =0), where the gene for cardiac ${beta}$ -myosinheavy chain is encoded. Analyses of this and other genes forsarcomere proteins identified disease-causing dominant mutationsin four kindreds. Cardiac ${beta}$ -myosin heavy-chain missense mutations(Ser532Pro and Phe764Leu) and a deletion in cardiac troponinT ( ${Delta}$ Lys210) caused early-onset ventricular dilatation (averageage at diagnosis, 24 years) and diminished contractile functionand frequently resulted in heart failure. Affected persons hadneither antecedent cardiac hypertrophy (average maximal left-ventricular-wallthickness, 8.5 mm) nor histopathological findings characteristicof hypertrophy.

Conclusions Mutations in sarcomere protein genes account forapproximately 10 percent of cases of familial dilated cardiomyopathyand are particularly prevalent in families with early-onsetventricular dilatation and dysfunction. Because distinct mutationsin sarcomere proteins cause either dilated or hypertrophic cardiomyopathy,the effects of mutant sarcomere proteins on muscle mechanicsmust trigger two different series of events that remodel theheart.

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From the Cardiovascular Division, Brigham and Women's Hospital, Boston (M.K., S.S., C.E.S.); the Department of Genetics, Harvard Medical School and Howard Hughes Medical Institute, Boston (M.K., S.D.S., S.R.D., P.S., B.M., J.G.S., C.E.S.); the Department of Cardiology, Children's Hospital, Boston (L.S., M.P.M.); the Cardiovascular Division, Massachusetts General Hospital, Boston (M.P.M.); the Department of Pediatrics, Westchester Medical Center, New York Medical College, Valhalla (P.K.W.); and the Department of Medicine, Toronto General Hospital, University of Toronto, Toronto (E.D.W.). Other authors were John Jarcho, M.D., Cardiovascular Division, Brigham and Women's Hospital, Boston; and Lawrence R. Shapiro, M.D., Department of Pediatrics, Westchester Medical Center, New York Medical College, Valhalla.Drs. Kamisago and S.D. Sharma contributed equally to the article.

Address reprint requests to Dr. Christine Seidman at the Department of Genetics, Harvard Medical School, Alpert Bldg., Rm. 533, 200 Longwood Ave., Boston, MA 02115, or at cseidman{at}rascal.med.harvard.edu.

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