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1 Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, Vermont, USA
2 Cardiovascular Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Bethesda, Maryland, USA
3 Dakota Cardiovascular, Rapid City, South Dakota, USA
* To whom correspondence should be addressed. E-mail: mohiddis{at}nhlbi.nih.gov.
Autosomal dominant familial hypertrophic cardiomyopathy (FHC) has variable penetrance and phenotype. Heterozygous mutations in MYH7, encoding 
-myosin heavy
chain, are the commonest causes of FHC, and we proposed that 'enhanced' mutant actinmyosin function is the causative molecular abnormality. We have studied individuals from families where members have two, one or no mutant MYH7 alleles to examine for dose effects. In one family, a member homozygous for Lys207Gln had cardiomyopathy complicated by left ventricular dilatation, systolic impairment, atrial fibrillation and
defibrillator interventions. Only one of five heterozygous relatives had FHC. Leu908Val and Asp906Gly mutations were detected in a second family in which penetrance for
Leu908Val heterozygotes was 46% (21/46) and 25% (3/12) for Asp906Gly. Despite the low penetrance, hypertrophy was severe in several heterozygotes. Two individuals with
both mutations developed severe FHC. The velocities of actin translocation (Vactin) by mutant and wild-type (WT) myosins were compared in the in-vitro motility assay. Compared to WT/WT, Vactin was 34% faster for WT/D906G and 21% for WT/L908V. Surprisingly Vactin for L908V/D906G and K207Q/K207Q mutants were similar to WT. However, the apparent enhancement of mechanical performance with mutant/WT myosin was not observed for mutant/mutant myosin. This suggests that Vactin may be a poor predictor of disease penetrance or severity and that power production may be more appropriate, or that the limited availability of double mutant patients prohibits any definitive conclusions. Finally, severe FHC in heterozygous individuals can occur despite very low penetrance suggesting these mutations alone are insufficient to cause FHC and that uncharacterized modifying mechanisms exert powerful influences.
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