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 C Doetschman, Gunter Grupp, Hanna Osinska, Timothy E. Hewett, Greg Boivin, James Gulick, Willie A. Ng, Jeffrey Robbins

Research output: Contribution to journalArticle

151 Citations (Scopus)

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
StatePublished - Oct 15 1996
Externally publishedYes

Fingerprint

Myosin Heavy Chains
Alleles
Genes
Contractile Proteins
Homologous Recombination
Heterozygote
Myocardium
Fibrosis
Mutation
Proteins

Keywords

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

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Jones, W. K., Grupp, I. L., Doetschman, T. C., Grupp, G., Osinska, H., Hewett, T. E., ... Robbins, J. (1996). Ablation of the murine α myosin heavy chain gene leads to dosage effects and functional deficits in the heart. Journal of Clinical Investigation, 98(8), 1906-1917.

Ablation of the murine α myosin heavy chain gene leads to dosage effects and functional deficits in the heart. / Jones, W. Keith; Grupp, Ingrid L.; Doetschman, Thomas C; Grupp, Gunter; Osinska, Hanna; Hewett, Timothy E.; Boivin, Greg; Gulick, James; Ng, Willie A.; Robbins, Jeffrey.

In: Journal of Clinical Investigation, Vol. 98, No. 8, 15.10.1996, p. 1906-1917.

Research output: Contribution to journalArticle

Jones, WK, Grupp, IL, Doetschman, TC, Grupp, G, Osinska, H, Hewett, TE, Boivin, G, Gulick, J, Ng, WA & Robbins, J 1996, 'Ablation of the murine α myosin heavy chain gene leads to dosage effects and functional deficits in the heart', Journal of Clinical Investigation, vol. 98, no. 8, pp. 1906-1917.
Jones, W. Keith ; Grupp, Ingrid L. ; Doetschman, Thomas C ; Grupp, Gunter ; Osinska, Hanna ; Hewett, Timothy E. ; Boivin, Greg ; Gulick, James ; Ng, Willie A. ; Robbins, Jeffrey. / Ablation of the murine α myosin heavy chain gene leads to dosage effects and functional deficits in the heart. In: Journal of Clinical Investigation. 1996 ; Vol. 98, No. 8. pp. 1906-1917.
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