Transgenic over-expression of a motor protein at high levels results in severe cardiac pathology

Jeanne James, Hanna Osinska, Timothy E. Hewett, Thomas Kimball, Raisa Klevitsky, Sandra Witt, D. Greg Hall, James Gulicki, Jeffre Robbins

Research output: Contribution to journalArticle

30 Scopus citations

Abstract

Transgenesis has become a useful tool in effecting a complete or partial remodeling of the cardiac contractile apparatus. Although gene dosage effects were initially a concern, recent data showed that the heart is able to accommodate varying levels of transgenic over-expression without detectable ill effects. The present study was designed to test the limits of the transgenic paradigm in terms of the production of a cardiac phenotype due simply to the over-expression of a contractile protein. To this end, eight lines of mice which express an isoform of the essential myosin light chain 1 that is normally found in the adult ventricle (ELClv) were generated. Overt phenotype was correlated both with the level of expression/protein replacement and copy number of the transgene. Two of the lines showed essentially complete replacement of the atrial isoform (ELCla) with ELClv. However, the phenotypes of the two lines differed dramatically. The line with the lower copy number (37 copies), and moderate over-expression (16 fold) showed no overt pathology while a line with very high copy number (94 copies) and extremely high levels of over-expression (27-50 fold) developed a significant atrial hypertrophy, dilation and cardiomyopathy. These data indicate that very high expression levels of a contractile protein can cause a cardiac pathology that is unrelated to its degree of replacement in the sarcomere and the unique role(s) it may assume in motor protein function.

Original languageEnglish (US)
Pages (from-to)9-22
Number of pages14
JournalTransgenic Research
Volume8
Issue number1
DOIs
StatePublished - Feb 1 1999

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Keywords

  • Gene
  • Muscle
  • Myosin light chain
  • Transgenesis

ASJC Scopus subject areas

  • Biotechnology
  • Animal Science and Zoology
  • Agronomy and Crop Science
  • Genetics

Cite this

James, J., Osinska, H., Hewett, T. E., Kimball, T., Klevitsky, R., Witt, S., Hall, D. G., Gulicki, J., & Robbins, J. (1999). Transgenic over-expression of a motor protein at high levels results in severe cardiac pathology. Transgenic Research, 8(1), 9-22. https://doi.org/10.1023/A:1008894507995