title: Hypertrophic cardiomyopathy in cardiac myosin binding protein-C knockout mice.
abstract: 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.
authors.affiliation: Department of Physiology, Section of Cardiovascular Medicine, University of Wisconsin Medical School, Madison, Wis 53706, USA. spharris@physiology.wisc.edu
authors.forename: Samantha P
authors.initials: SP
authors.lastname: Harris
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Bartley
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Hacker
authors.forename: Kerry S
authors.initials: KS
authors.lastname: McDonald
authors.forename: Pamela S
authors.initials: PS
authors.lastname: Douglas
authors.forename: Marion L
authors.initials: ML
authors.lastname: Greaser
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Powers
authors.forename: Richard L
authors.initials: RL
authors.lastname: Moss
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects / Q000502:physiology; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002118:Calcium / Q000494:pharmacology; D002312:Cardiomyopathy, Hypertrophic / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D004452:Echocardiography; D018390:Gene Targeting; D006579:Heterozygote; D006720:Homozygote; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D010641:Phenotype; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018487:Ventricular Dysfunction, Left / Q000209:etiology; D000099163:Myosin Binding Protein C
chemical_list: D002118:Calcium; D002352:Carrier Proteins; D012333:RNA, Messenger; D000099163:Myosin Binding Protein C