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.
McConnell
B K
BK
Department of Genetics, Howard Hughes Medical Institute and Harvard Medical School, Boston, Massachusetts 02115, USA.
Jones
K A
KA
Fatkin
D
D
Arroyo
L H
LH
Lee
R T
RT
Aristizabal
O
O
Turnbull
D H
DH
Georgakopoulos
D
D
Kass
D
D
Bond
M
M
Niimura
H
H
Schoen
F J
FJ
Conner
D
D
Fischman
D A
DA
Seidman
C E
CE
Seidman
J G
JG
Fischman
D H
DH
D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D015152:Blotting, Northern; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000503:physiopathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D005838:Genotype; D006321:Heart / Q000033:anatomy & histology / Q000503:physiopathology; D006720:Homozygote; D051379:Mice; D008817:Mice, Mutant Strains; D008854:Microscopy, Electron; D008969:Molecular Sequence Data; D016254:Mutagenesis, Insertional; D009154:Mutation; D009206:Myocardium / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012518:Sarcomeres / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D000099163:Myosin Binding Protein C
D002352:Carrier Proteins; D012333:RNA, Messenger; D000099163:Myosin Binding Protein C