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Hypertrophic cardiomyopathy in cardiac myosin binding protein-C knockout mice.

Publication ,  Journal Article
Harris, SP; Bartley, CR; Hacker, TA; McDonald, KS; Douglas, PS; Greaser, ML; Powers, PA; Moss, RL
Published in: Circ Res
March 22, 2002

Familial hypertrophic cardiomyopathy (FHC) is an inherited autosomal dominant disease caused by mutations in sarcomeric proteins. Among these, mutations that affect myosin binding protein-C (MyBP-C), an abundant component of the thick filaments, account for 20% to 30% of all mutations linked to FHC. However, the mechanisms by which MyBP-C mutations cause disease and the function of MyBP-C are not well understood. Therefore, to assess deficits due to elimination of MyBP-C, we used gene targeting to produce a knockout mouse that lacks MyBP-C in the heart. Knockout mice were produced by deletion of exons 3 to 10 from the endogenous cardiac (c) MyBP-C gene in murine embryonic stem (ES) cells and subsequent breeding of chimeric founder mice to obtain mice heterozygous (+/-) and homozygous (-/-) for the knockout allele. Wild-type (+/+), cMyBP-C(+/-), and cMyBP-C(-/-) mice were born in accordance with Mendelian inheritance ratios, survived into adulthood, and were fertile. Western blot analyses confirmed that cMyBP-C was absent in hearts of homozygous knockout mice. Whereas cMyBP-C(+/-) mice were indistinguishable from wild-type littermates, cMyBP-C(-/-) mice exhibited significant cardiac hypertrophy. Cardiac function, assessed using 2-dimensionally guided M-mode echocardiography, showed significantly depressed indices of diastolic and systolic function only in cMyBP-C(-/-) mice. Ca2+ sensitivity of tension, measured in single skinned myocytes, was reduced in cMyBP-C(-/-) but not cMyBP-C(+/-) mice. These results establish that cMyBP-C is not essential for cardiac development but that the absence of cMyBP-C results in profound cardiac hypertrophy and impaired contractile function.

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Published In

Circ Res

DOI

EISSN

1524-4571

Publication Date

March 22, 2002

Volume

90

Issue

5

Start / End Page

594 / 601

Location

United States

Related Subject Headings

  • Ventricular Dysfunction, Left
  • Reverse Transcriptase Polymerase Chain Reaction
  • RNA, Messenger
  • Phenotype
  • Myocardium
  • Muscle, Skeletal
  • Mice, Knockout
  • Mice
  • In Vitro Techniques
  • Homozygote
 

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Harris, S. P., Bartley, C. R., Hacker, T. A., McDonald, K. S., Douglas, P. S., Greaser, M. L., … Moss, R. L. (2002). Hypertrophic cardiomyopathy in cardiac myosin binding protein-C knockout mice. Circ Res, 90(5), 594–601. https://doi.org/10.1161/01.res.0000012222.70819.64
Harris, Samantha P., Christopher R. Bartley, Timothy A. Hacker, Kerry S. McDonald, Pamela S. Douglas, Marion L. Greaser, Patricia A. Powers, and Richard L. Moss. “Hypertrophic cardiomyopathy in cardiac myosin binding protein-C knockout mice.Circ Res 90, no. 5 (March 22, 2002): 594–601. https://doi.org/10.1161/01.res.0000012222.70819.64.
Harris SP, Bartley CR, Hacker TA, McDonald KS, Douglas PS, Greaser ML, et al. Hypertrophic cardiomyopathy in cardiac myosin binding protein-C knockout mice. Circ Res. 2002 Mar 22;90(5):594–601.
Harris, Samantha P., et al. “Hypertrophic cardiomyopathy in cardiac myosin binding protein-C knockout mice.Circ Res, vol. 90, no. 5, Mar. 2002, pp. 594–601. Pubmed, doi:10.1161/01.res.0000012222.70819.64.
Harris SP, Bartley CR, Hacker TA, McDonald KS, Douglas PS, Greaser ML, Powers PA, Moss RL. Hypertrophic cardiomyopathy in cardiac myosin binding protein-C knockout mice. Circ Res. 2002 Mar 22;90(5):594–601.

Published In

Circ Res

DOI

EISSN

1524-4571

Publication Date

March 22, 2002

Volume

90

Issue

5

Start / End Page

594 / 601

Location

United States

Related Subject Headings

  • Ventricular Dysfunction, Left
  • Reverse Transcriptase Polymerase Chain Reaction
  • RNA, Messenger
  • Phenotype
  • Myocardium
  • Muscle, Skeletal
  • Mice, Knockout
  • Mice
  • In Vitro Techniques
  • Homozygote