Ablation of the murine α myosin heavy chain gene leads to dosage effects and functional deficits in the heart

W. Keith Jones, Ingrid L. Grupp, Thomas Doetschman, Gunter Grupp, Hanna Osinska, Timothy E. Hewett, Greg Boivin, James Gulick, Willie A. Ng, Jeffrey Robbins

Research output: Contribution to journalArticlepeer-review

155 Scopus citations

Abstract

The α-myosin heavy chain (α-MyHC) is the major contractile protein expressed in the myocardium of adult mice. We have produced mice carrying a null mutation of α-MyHC by homologous recombination in murine ES cells. Homozygous null animals die between 11 and 12 d in utero of gross heart defects, while α-MyHC(+/-) heterozygotes survive and appear externally normal. The presence of a single functional α-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 α-MyHC(+/-) animals. Thus, two α-MyHC+ alleles are necessary for normal cardiac development, and hemizygosity for the normal allele can result in altered cardiac function.

Original languageEnglish (US)
Pages (from-to)1906-1917
Number of pages12
JournalJournal of Clinical Investigation
Volume98
Issue number8
DOIs
StatePublished - Oct 15 1996

Keywords

  • embryonic stem cells
  • gene dosage
  • gene targeting
  • left ventricular function
  • myofibrils
  • myosin

ASJC Scopus subject areas

  • Medicine(all)

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