Functional analysis of myosin mutations that cause familial hypertrophic cardiomyopathy

Osha Roopnarine, Leslie A. Leinwand

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Abstract

We have studied-the actin-activated ATPase activities of three mutations in the motor domain of the myosin heavy chain that cause familial hypertrophic cardiomyopathy. We placed these mutations in rodent α-cardiac myosin to establish the relevance of using rodent systems for studying the biochemical mechanisms of the human disease. We also wished to determine whether the biochemical defects in these mutant alleles correlate with the severity of the clinical phenotype of patients with these alleles. We expressed histidine-tagged rat cardiac myosin motor domains along with rat ventricular light chain 1 in mammalian COS cells. Those myosins studied were wild-type α-cardiac and three mutations in the α-cardiac myosin heavy chain head (Arg249Gln, Arg403Gln, and Val606Met). These mutations in human β-cardiac myosin heavy chain have predominantly moderate, severe, and mild clinical phenotypes, respectively. The crystal structure of the skeletal myosin head shows that the Arg249Gln mutation is near the ATP-binding site and the Arg403Gln and Val606Met mutations are in the actin-binding region. Expressed histidine-tagged α-motor domains retain physiological ATPase properties similar to those derived from cardiac tissue. All three myosin-mutants show defects in the ATPase activity, with the degree of enzymatic impairment of the mutant myosins correlated with the clinical phenotype of patients with the disease caused by the corresponding mutation.

Original languageEnglish (US)
Pages (from-to)3023-3030
Number of pages8
JournalBiophysical journal
Volume75
Issue number6
DOIs
StatePublished - Dec 1998

Bibliographical note

Funding Information:
This work was supported by postdoctoral fellowships from the Muscular Dystrophy Association and the American Heart Association of the Colorado and Wyoming Affiliate to OR and by grants from the National Institutes of Health (HL50560-04 and GM29090-16) to LAL.

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