A mouse model of myosin binding protein C human familial hypertrophic cardiomyopathy.
Familial hypertrophic cardiomyopathy can be caused by mutations in genes encoding sarcomeric proteins, including the cardiac isoform of myosin binding protein C (MyBP-C), and multiple mutations which cause truncated forms of the protein to be made are linked to the disease. We have created transgenic mice in which varying amounts of a mutated MyBP-C, lacking the myosin and titin binding domains, are expressed in the heart. The transgenically encoded, truncated protein is stable but is not incorporated efficiently into the sarcomere. The transgenic muscle fibers showed a leftward shift in the pCa2+-force curve and, importantly, their power output was reduced. Additionally, expression of the mutant protein leads to decreased levels of endogenous MyBP-C, resulting in a striking pattern of sarcomere disorganization and dysgenesis.
Department of Pediatrics, Division of Molecular Cardiovascular Biology, Children's Hospital Research Foundation, Cincinnati, Ohio 45229-3039, USA.
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Q
Yang
A
A
Sanbe
H
H
Osinska
T E
TE
Hewett
R
R
Klevitsky
J
J
Robbins
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics* / Q000473:pathology; D002352:Carrier Proteins / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics*; D006321:Heart / Q000503:physiopathology; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D018485:Muscle Fibers, Skeletal / Q000473:pathology / Q000502:physiology / Q000648:ultrastructure; D016297:Mutagenesis, Site-Directed; D009206:Myocardium / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D009218:Myosins / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012518:Sarcomeres / Q000473:pathology / Q000502:physiology / Q000648:ultrastructure; D017384:Sequence Deletion; D014158:Transcription, Genetic; D000099163:Myosin Binding Protein C
D002118:Calcium; D002352:Carrier Proteins; D009218:Myosins; D000099163:Myosin Binding Protein C