In vivo analysis of an essential myosin light chain mutation linked to familial hypertrophic cardiomyopathy

Atsushi Sanbe, David Nelson, James Gulick, Elizabeth Setser, Hanna Osinska, Xuejun Wang, Timothy E. Hewett, Raisa Klevitsky, Eric Hayes, David M. Warshaw, Jeffrey Robbins

Research output: Contribution to journalArticlepeer-review

40 Scopus citations


Mutations in cardiac motor protein genes are associated with familial hypertrophic cardiomyopathy. Mutations in both the regulatory (Glu22Lys) and essential light chains (Met149Val) result in an unusual pattern of hypertrophy, leading to obstruction of the midventricular cavity. When a human genomic fragment containing the Met149Val essential myosin light chain was used to generate transgenic mice, the phenotype was recapitulated. To unambiguously establish a causal relationship for the regulatory and essential light chain mutations in hypertrophic cardiomyopathy, we generated mice that expressed either the wild-type or mutated forms, using cDNA clones encompassing only the coding regions of the gene loci. Expression of the proteins did not lead to a hypertrophic response, even in senescent animals. Changes did occur at the myofilament and cellular levels, with the myofibrils showing increased Ca2+ sensitivity and significant deficits in relaxation in a transgene dose-dependent manner. Clearly, mice do not always recapitulate important aspects of human hypertrophy. However, because of the discordance of these data with data obtained in transgenic mice containing the human genomic fragment, we believe that the concept that these point mutations by themselves can cause hypertrophic cardiomyopathy should be revisited.

Original languageEnglish (US)
Pages (from-to)296-302
Number of pages7
JournalCirculation Research
Issue number4
StatePublished - Aug 18 2000
Externally publishedYes


  • Heart
  • Hypertrophy
  • Mouse
  • Muscle
  • Myosin

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine


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