Molecular and phenotypic effects of heterozygous, homozygous, and compound heterozygote myosin heavy-chain mutations

• Published in: American journal of physiology. Heart and circulatory physiology 2005-03, Vol.288 (3), p.H1097-H1102
• Main Authors: Alpert, Norman R, Mohiddin, Saidi A, Tripodi, Dorothy, Jacobson-Hatzell, Jacqueline, Vaughn-Whitley, Kelly, Brosseau, Christine, Warshaw, David M, Fananapazir, Lameh
• Format: Article
• Language: English
• Subjects: Actins - metabolism; Biopsy; Cardiomyopathy, Hypertrophic, Familial - genetics; Cardiomyopathy, Hypertrophic, Familial - physiopathology; Family Leave; Female; Heterozygote; Homozygote; Humans; Male; Muscle Contraction - genetics; Muscle, Skeletal - pathology; Muscle, Skeletal - physiology; Myosin Heavy Chains - genetics; Myosin Heavy Chains - physiology; Pedigree; Penetrance; Phenotype
• ISSN: 0363-6135; 1522-1539
• DOI: 10.1152/ajpheart.00650.2004

1 Department of Molecular Physiology and Biophysics, University of Vermont, Burlington, Vermont; 2 Cardiovascular Branch, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland; and 3 Dakota Cardiovascular, Physician Corporation, Rapid City, South Dakota Submitted 30 June 2004 ; accepted in final form 28 October 2004 Autosomal dominant familial hypertrophic cardiomyopathy (FHC) has variable penetrance and phenotype. Heterozygous mutations in MYH7 encoding -myosin heavy chain are the most common causes of FHC, and we proposed that "enhanced" mutant actin-myosin function is the causative molecular abnormality. We have studied individuals from families in which 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 ( V actin ) by mutant and wild-type (WT) myosins were compared in the in vitro motility assay. Compared with WT/WT, V actin was 34% faster for WT/D906G and 21% for WT/L908V. Surprisingly V actin for Leu908Val/Asp906Gly and Lys207Gln/Lys207Gln mutants were similar to WT. The apparent enhancement of mechanical performance with mutant/WT myosin was not observed for mutant/mutant myosin. This suggests that V actin 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. hypertrophy; cardiomyopathy; motility assay; penetrance Address for reprint requests and other correspondence: S. A. Mohiddin, Rm. 5-5330, Bldg 10 CRC, 10 Center Dr., Bethesda, MD 20892 (E-mail: mohiddis{at}nhlbi.nih.gov )