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 protein 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 utero of gross heart defects, while alpha-MyHC+/- heterozygotes survive and appear externally normal. The presence of a single functional alpha-MyHC+ allele in heterozygous animals results in reduced levels of the transcript and protein as well as fibrosis and alterations in sarcomeric structure. Examination of heart function using a working heart preparation revealed severe impairment of both contractility and relaxation in a subset of the alpha-MyHC+/- animals. Thus, two alpha-MyHC+ alleles are necessary for normal cardiac development, and hemizygosity for the normal allele can result in altered cardiac function.
Jones
W K
WK
Division of Molecular Cardiovascular Biology, Children's Hospital Research Foundation, Cincinnati, Ohio 45229-3039, USA.
Grupp
I L
IL
Doetschman
T
T
Grupp
G
G
Osinska
H
H
Hewett
T E
TE
Boivin
G
G
Gulick
J
J
Ng
W A
WA
Robbins
J
J
D000483:Alleles; D000818:Animals; D001483:Base Sequence; D018628:Gene Dosage; D018390:Gene Targeting; D006321:Heart / Q000502:physiology*; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009206:Myocardium / Q000473:pathology / Q000648:ultrastructure; D018995:Myosin Heavy Chains / Q000235:genetics*; D016277:Ventricular Function, Left
D018995:Myosin Heavy Chains