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Cardiovascular Genetics Center
Dilated cardiomyopathy in homozygous myosin-binding protein-C mutant mice
To elucidate the role of cardiac myosin-binding protein-C (MyBP-C) in myocardial
structure and function, we have produced mice expressing altered forms of this
sarcomere protein. The engineered mutations encode truncated forms of MyBP-C in
which the cardiac myosin heavy chain-binding and titin-binding domain has been
replaced with novel amino acid residues. Analogous heterozygous defects in
humans cause hypertrophic cardiomyopathy. Mice that are homozygous for the
mutated MyBP-C alleles express less than 10% of truncated protein in M-bands of
otherwise normal sarcomeres. Homozygous mice bearing mutated MyBP-C alleles are
viable but exhibit neonatal onset of a progressive dilated cardiomyopathy with
prominent histopathology of myocyte hypertrophy, myofibrillar disarray,
fibrosis, and dystrophic calcification. Echocardiography of homozygous mutant
mice showed left ventricular dilation and reduced contractile function at birth;
myocardial hypertrophy increased as the animals matured. Left-ventricular
pressure-volume analyses in adult homozygous mutant mice demonstrated depressed
systolic contractility with diastolic dysfunction. These data revise our
understanding of the role that MyBP-C plays in myofibrillogenesis during cardiac
development and indicate the importance of this protein for long-term sarcomere
function and normal cardiac morphology. We also propose that mice bearing
homozygous familial hypertrophic cardiomyopathy-causing mutations may provide
useful tools for predicting the severity of disease that these mutations will
cause in humans.
Citation: J Clin Invest 1999 Nov;104(9):1235-44
Read complete publication at: http://www.jci.org/cgi/content/full/104/9/1235?view=full&pmid=10545522.html
Authors not members of the CardioGenomics PGA
McConnell BK, Jones KA, Fatkin D, Arroyo LH, Lee RT, Aristizabal O, Turnbull DH,
Georgakopoulos D, Kass D, Bond M, Niimura H, Schoen FJ, Conner D, Fischman DA
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