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PMID: 9769321 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

A mouse model of myosin binding protein C human familial hypertrophic cardiomyopathy.

The Journal of clinical investigation ·Vol. 102 ·No. 7 ·1998-10-01 ·Pages 1292-300

Yang Q, Sanbe A, Osinska H, Hewett TE, Klevitsky R, Robbins J

Abstract

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.

MeSH Terms
Animals Calcium/metabolism Cardiomyopathy, Hypertrophic/genetics,pathology Carrier Proteins/analysis,biosynthesis,genetics Heart/physiopathology Humans Mice Mice, Transgenic Muscle Fibers, Skeletal/pathology,physiology,ultrastructure Mutagenesis, Site-Directed Myocardium/metabolism,pathology,ultrastructure Myosins/metabolism Reverse Transcriptase Polymerase Chain Reaction Sarcomeres/pathology,physiology,ultrastructure Sequence Deletion Transcription, Genetic
Chemicals
Carrier Proteins myosin-binding protein C Myosins Calcium
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Yang Q
Department of Pediatrics, Division of Molecular Cardiovascular Biology, Children's Hospital Research Foundation, Cincinnati, Ohio 45229-3039, USA.
Sanbe A
Osinska H
Hewett T E
Klevitsky R
Robbins J
References (36)
36 references, click to expand
  1. Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy.
    N Engl J Med. 1998 Apr 30;338(18):1248-57 PMID: 9562578
  2. Identification of a new missense mutation in MyBP-C associated with hypertrophic cardiomyopathy.
    J Med Genet. 1998 Mar;35(3):253-4 PMID: 9541115
  3. A new protein of the thick filaments of vertebrate skeletal myofibrils. Extractions, purification and characterization.
    J Mol Biol. 1973 Mar 15;74(4):653-76 PMID: 4269687
  4. The velocity of unloaded shortening and its relation to sarcomere length and isometric force in vertebrate muscle fibres.
    J Physiol. 1979 Jun;291:143-59 PMID: 314510
  5. Effects on shortening velocity of rabbit skeletal muscle due to variations in the level of thin-filament activation.
    J Physiol. 1986 Aug;377:487-505 PMID: 3795099
  6. A molecular basis for familial hypertrophic cardiomyopathy: a beta cardiac myosin heavy chain gene missense mutation.
    Cell. 1990 Sep 7;62(5):999-1006 PMID: 1975517
  7. Cardiac myosin heavy chain mRNA expression and myocardial function in the mouse heart.
    Circ Res. 1991 Jun;68(6):1742-50 PMID: 2036722
  8. Troponin T expression in normal and pressure-loaded fetal sheep heart.
    Pediatr Res. 1991 Jun;29(6):580-5 PMID: 1866215
  9. Determinants of loaded shortening velocity in single cardiac myocytes permeabilized with alpha-hemolysin.
    Circ Res. 1993 Dec;73(6):1150-62 PMID: 8222086
  10. The major myosin-binding domain of skeletal muscle MyBP-C (C protein) resides in the COOH-terminal, immunoglobulin C2 motif.
    J Cell Biol. 1993 Nov;123(3):619-26 PMID: 8227129
  11. Alpha-tropomyosin and cardiac troponin T mutations cause familial hypertrophic cardiomyopathy: a disease of the sarcomere.
    Cell. 1994 Jun 3;77(5):701-12 PMID: 8205619
  12. Autoimmune myocarditis induced in mice by cardiac C-protein. Cloning of complementary DNA encoding murine cardiac C-protein and partial characterization of the antigenic peptides.
    J Clin Invest. 1994 Sep;94(3):1026-36 PMID: 8083344
  13. Multiple disease genes cause hypertrophic cardiomyopathy.
    Br Heart J. 1994 Dec;72(6 Suppl):S4-9 PMID: 7873324
  14. Mutations in the genes for cardiac troponin T and alpha-tropomyosin in hypertrophic cardiomyopathy.
    N Engl J Med. 1995 Apr 20;332(16):1058-64 PMID: 7898523
  15. Familial hypertrophic cardiomyopathy. Nonsense versus missense mutations.
    Circulation. 1995 Jun 15;91(12):2865-7 PMID: 7796493
  16. Familial Hypertrophic cardiomyopathy with Wolff-Parkinson-White syndrome maps to a locus on chromosome 7q3.
    J Clin Invest. 1995 Sep;96(3):1216-20 PMID: 7657794
  17. Mutations in the cardiac myosin binding protein-C gene on chromosome 11 cause familial hypertrophic cardiomyopathy.
    Nat Genet. 1995 Dec;11(4):434-7 PMID: 7493025
  18. Cardiac myosin binding protein-C gene splice acceptor site mutation is associated with familial hypertrophic cardiomyopathy.
    Nat Genet. 1995 Dec;11(4):438-40 PMID: 7493026
  19. Transgenic remodeling of the contractile apparatus in the mammalian heart.
    Circ Res. 1996 Mar;78(3):504-9 PMID: 8593710
  20. A mouse model of familial hypertrophic cardiomyopathy.
    Science. 1996 May 3;272(5262):731-4 PMID: 8614836
  21. A molecular map of the interactions between titin and myosin-binding protein C. Implications for sarcomeric assembly in familial hypertrophic cardiomyopathy.
    Eur J Biochem. 1996 Jan 15;235(1-2):317-23 PMID: 8631348
  22. Mutations in either the essential or regulatory light chains of myosin are associated with a rare myopathy in human heart and skeletal muscle.
    Nat Genet. 1996 May;13(1):63-9 PMID: 8673105
  23. Triggers for sudden cardiac death in the athlete.
    Cardiol Clin. 1996 May;14(2):195-210 PMID: 8724552
  24. Modulation of myosin filament organization by C-protein family members.
    Mol Biol Cell. 1996 Jan;7(1):113-27 PMID: 8741844
  25. Titin as a scaffold and spring. Cytoskeleton.
    Curr Biol. 1996 Mar 1;6(3):258-60 PMID: 8805236
  26. The carboxyl terminus of myosin binding protein C (MyBP-C, C-protein) specifies incorporation into the A-band of striated muscle.
    J Cell Sci. 1996 Jan;109 ( Pt 1):101-11 PMID: 8834795
  27. Ablation of the murine alpha myosin heavy chain gene leads to dosage effects and functional deficits in the heart.
    J Clin Invest. 1996 Oct 15;98(8):1906-17 PMID: 8878443
  28. Mice expressing mutant myosin heavy chains are a model for familial hypertrophic cardiomyopathy.
    Mol Med. 1996 Sep;2(5):556-67 PMID: 8898372
  29. Organization and sequence of human cardiac myosin binding protein C gene (MYBPC3) and identification of mutations predicted to produce truncated proteins in familial hypertrophic cardiomyopathy.
    Circ Res. 1997 Mar;80(3):427-34 PMID: 9048664
  30. Transgenic remodeling of the regulatory myosin light chains in the mammalian heart.
    Circ Res. 1997 May;80(5):655-64 PMID: 9130446
  31. Novel splice donor site mutation in the cardiac myosin-binding protein-C gene in familial hypertrophic cardiomyopathy. Characterization Of cardiac transcript and protein.
    J Clin Invest. 1997 Jul 15;100(2):475-82 PMID: 9218526
  32. Mutations in the cardiac troponin I gene associated with hypertrophic cardiomyopathy.
    Nat Genet. 1997 Aug;16(4):379-82 PMID: 9241277
  33. A treadmill exercise regimen for identifying cardiovascular phenotypes in transgenic mice.
    Am J Physiol. 1997 Sep;273(3 Pt 2):H1595-605 PMID: 9321854
  34. Genotype-phenotype correlations in familial hypertrophic cardiomyopathy. A comparison between mutations in the cardiac protein-C and the beta-myosin heavy chain genes.
    Eur Heart J. 1998 Jan;19(1):139-45 PMID: 9503187
  35. Molecular pathology of familial hypertrophic cardiomyopathy caused by mutations in the cardiac myosin binding protein C gene.
    J Med Genet. 1998 Mar;35(3):205-10 PMID: 9541104
  36. Functional significance of cardiac myosin essential light chain isoform switching in transgenic mice.
    J Clin Invest. 1998 Jun 15;101(12):2630-9 PMID: 9637696
Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI3880
Published
1998-10-01
Pages
1292-300
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC508976
Subset
IM
Grants
NHLBI NIH HHS · HL-41496 · United States
NHLBI NIH HHS · HL-52318 · United States
NHLBI NIH HHS · HL-56370 · United States
External Links
PubMed source DOI: 10.1172/JCI3880 PMC Full Text View journal details
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