Document Detail


Myosin regulatory light chain mutation found in hypertrophic cardiomyopathy patients increases isometric force production in transgenic mice.
MedLine Citation:
PMID:  22091967     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
FHC (familial hypertrophic cardiomyopathy) is a heritable form of cardiac hypertrophy caused by mutations in genes encoding sarcomeric proteins. The present study focuses on the A13T mutation in the human ventricular myosin RLC (regulatory light chain) that is associated with a rare FHC variant defined by mid-ventricular obstruction and septal hypertrophy. We generated heart-specific Tg (transgenic) mice with ~10% of human A13T-RLC mutant replacing the endogenous mouse cardiac RLC. Histopathological examinations of longitudinal heart sections from Tg-A13T mice showed enlarged interventricular septa and profound fibrotic lesions compared with Tg-WT (wild-type), expressing the human ventricular RLC, or non-Tg mice. Functional studies revealed an abnormal A13T mutation-induced increase in isometric force production, no change in the force-pCa relationship and a decreased Vmax of the acto-myosin ATPase. In addition, a fluorescence-based assay showed a 3-fold lower binding affinity of the recombinant A13T mutant for the RLC-depleted porcine myosin compared with WT-RLC. These results suggest that the A13T mutation triggers a hypertrophic response through changes in cardiac sarcomere organization and myosin cross-bridge function leading to abnormal remodelling of the heart. The significant functional changes observed, despite a low level of A13T mutant incorporation into myofilaments, suggest a 'poison-peptide' mechanism of disease.
Authors:
Katarzyna Kazmierczak; Priya Muthu; Wenrui Huang; Michelle Jones; Yingcai Wang; Danuta Szczesna-Cordary
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Biochemical journal     Volume:  442     ISSN:  1470-8728     ISO Abbreviation:  Biochem. J.     Publication Date:  2012 Feb 
Date Detail:
Created Date:  2012-01-27     Completed Date:  2012-03-25     Revised Date:  2014-09-18    
Medline Journal Info:
Nlm Unique ID:  2984726R     Medline TA:  Biochem J     Country:  England    
Other Details:
Languages:  eng     Pagination:  95-103     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Animals
Cardiomyopathy, Hypertrophic, Familial / genetics*,  pathology,  physiopathology
Humans
Male
Mice
Mice, Transgenic
Mutation
Myocardial Contraction / genetics,  physiology*
Myocardium / pathology
Myofibrils / genetics
Myosin Light Chains / genetics*,  physiology
Papillary Muscles / pathology
Rabbits
Sarcomeres / ultrastructure
Swine
Grant Support
ID/Acronym/Agency:
HL071778/HL/NHLBI NIH HHS; HL090786/HL/NHLBI NIH HHS; R01 HL071778/HL/NHLBI NIH HHS; R01 HL071778-01A1/HL/NHLBI NIH HHS; R01 HL071778-07/HL/NHLBI NIH HHS; R01 HL071778-08/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Myosin Light Chains

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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