Published Online
on May 6, 2002

A more recent version of this article appeared on May 21, 2002

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Submitted on February 7, 2002
Revised on April 3, 2002
Accepted on April 3, 2002

Myosin Light Chain Mutation Causes Autosomal Recessive Cardiomyopathy With Mid-Cavitary Hypertrophy and Restrictive Physiology

Timothy M. Olson MD^*, Margaret L. Karst BA, Frank G. Whitby PhD, and David J. Driscoll MD

From the Departments of Medicine, Division of Cardiovascular Diseases (T.M.O., M.L.K.) and Pediatric and Adolescent Medicine, Division of Cardiology (T.M.O., D.J.D.), Mayo Clinic, Rochester, Minn; and the Department of Biochemistry (F.G.W.), University of Utah, Salt Lake City.

^* To whom correspondence should be addressed. E-mail: olson.timothy{at}mayo.edu.

Background—Autosomal dominant hypertrophic cardiomyopathy (HCM) is caused by inherited defects of sarcomeric proteins. We tested the hypothesis that homozygosity for a sarcomeric protein defect can cause recessive HCM.

Methods and Results—We studied a family with early-onset cardiomyopathy in 3 siblings, characterized by mid-cavitary hypertrophy and restrictive physiology. Genotyping of DNA markers spanning 8 genes for autosomal dominant HCM revealed inheritance of an identical paternal and maternal haplotype at the essential light chain of myosin locus by the affected children. Sequencing showed that these individuals were homozygous for a Glu143Lys substitution of a highly conserved amino acid that was absent in 150 controls. Family members with one Glu143Lys allele had normal echocardiograms and ECGs, even in late adulthood, whereas those with two mutant alleles developed severe cardiomyopathy in childhood. These findings, coupled with previous studies of myosin light chain structure and function in the heart, suggest a loss-of-function disease mechanism.

Conclusions—Distinct mutations affecting the same sarcomeric protein can cause either dominant or recessive cardiomyopathy. Electrostatic charge reversal of a highly conserved amino acid may be benign in the heterozygous state as the result of compensatory mechanisms that preserve cardiac structure and function. By contrast, homozygous carriers of a sarcomeric protein defect may have a malignant course. Recognizing recessive inheritance in children with cardiomyopathy is essential for appropriate family counseling.

Key words: genetics • cardiomyopathy • myosin

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