title: Dilated cardiomyopathy in homozygous myosin-binding protein-C mutant mice.
abstract: 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.
authors.affiliation: Department of Genetics, Howard Hughes Medical Institute and Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: B K
authors.initials: BK
authors.lastname: McConnell
authors.forename: K A
authors.initials: KA
authors.lastname: Jones
authors.forename: D
authors.initials: D
authors.lastname: Fatkin
authors.forename: L H
authors.initials: LH
authors.lastname: Arroyo
authors.forename: R T
authors.initials: RT
authors.lastname: Lee
authors.forename: O
authors.initials: O
authors.lastname: Aristizabal
authors.forename: D H
authors.initials: DH
authors.lastname: Turnbull
authors.forename: D
authors.initials: D
authors.lastname: Georgakopoulos
authors.forename: D
authors.initials: D
authors.lastname: Kass
authors.forename: M
authors.initials: M
authors.lastname: Bond
authors.forename: H
authors.initials: H
authors.lastname: Niimura
authors.forename: F J
authors.initials: FJ
authors.lastname: Schoen
authors.forename: D
authors.initials: D
authors.lastname: Conner
authors.forename: D A
authors.initials: DA
authors.lastname: Fischman
authors.forename: C E
authors.initials: CE
authors.lastname: Seidman
authors.forename: J G
authors.initials: JG
authors.lastname: Seidman
authors.forename: D H
authors.initials: DH
authors.lastname: Fischman
mesh_terms: 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
chemical_list: D002352:Carrier Proteins; D012333:RNA, Messenger; D000099163:Myosin Binding Protein C