ABLATION OF THE MURINE ALPHA-MYOSIN HEAVY-CHAIN GENE LEADS TO DOSAGE EFFECTS AND FUNCTIONAL DEFICITS IN THE HEART

The alpha-myosin heavy chain (alpha-MyHC) is the major contractile pro tein expressed in the myocardium of adult mice. We have produced mice carrying a null mutation of alpha-MyHC by homologous recombination in murine ES cells, Homozygous null animals die between 11 and 12 d in ut ero of gross heart defects, while alpha-MyHC(+/-) heterozygotes surviv e and appear externally normal. The presence of a single functional al pha-MyHC(+) allele in heterozygous animals results in reduced levels o f the transcript and protein as well as fibrosis and alterations in sa rcomeric structure. Examination of heart function using a working hear t preparation revealed severe impairment of both contractility and rel axation in a subset of the alpha-MyHC(+/-) animals. Thus, two alpha-My HC(+) alleles are necessary for normal cardiac development, and hemizy gosity for the normal allele can result in altered cardiac function.