title: The E22K mutation of myosin RLC that causes familial hypertrophic cardiomyopathy increases calcium sensitivity of force and ATPase in transgenic mice.
abstract: Familial hypertrophic cardiomyopathy (FHC) is an autosomal dominant disease caused by mutations in all of the major sarcomeric proteins, including the ventricular myosin regulatory light-chain (RLC). The E22K-RLC mutation has been associated with a rare variant of cardiac hypertrophy defined by mid-left ventricular obstruction due to papillary muscle hypertrophy. This mutation was later found to cause ventricular and septal hypertrophy. We have generated transgenic (Tg) mouse lines of myc-WT (wild type) and myc-E22K mutant of human ventricular RLC and have examined the functional consequences of this FHC mutation in skinned cardiac-muscle preparations. In longitudinal sections of whole mouse hearts stained with hematoxylin and eosin, the E22K-mutant hearts of 13-month-old animals showed signs of inter-ventricular septal hypertrophy and enlarged papillary muscles with no filament disarray. Echo examination did not reveal evidence of cardiac hypertrophy in Tg-E22K mice compared to Tg-WT or Non-Tg hearts. Physiological studies utilizing skinned cardiac-muscle preparations showed an increase by DeltapCa50>or=0.1 in Ca(2+) sensitivity of myofibrillar ATPase activity and force development in Tg-E22K mice compared with Tg-WT or Non-Tg littermates. Our results suggest that E22K-linked FHC is mediated through Ca(2+)-dependent events. The FHC-mediated structural perturbations in RLC that affect Ca(2+) binding properties of the mutated myocardium are responsible for triggering the abnormal function of the heart that in turn might initiate a hypertrophic process and lead to heart failure.
authors.affiliation: Department of Molecular and Cellular Pharmacology, University of Miami School of Medicine, Miami, FL 33136, USA. dszczesna@med.miami.edu
authors.forename: Danuta
authors.initials: D
authors.lastname: Szczesna-Cordary
authors.forename: Georgianna
authors.initials: G
authors.lastname: Guzman
authors.forename: Jiaju
authors.initials: J
authors.lastname: Zhao
authors.forename: Olga
authors.initials: O
authors.lastname: Hernandez
authors.forename: Jianqin
authors.initials: J
authors.lastname: Wei
authors.forename: Zoraida
authors.initials: Z
authors.lastname: Diaz-Perez
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000235:genetics*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D004452:Echocardiography; D006801:Humans; D017379:Hypertrophy, Left Ventricular / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D051379:Mice; D008822:Mice, Transgenic; D009119:Muscle Contraction / Q000235:genetics*; D009154:Mutation / Q000235:genetics; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism; D018994:Myosin Light Chains / Q000235:genetics*
chemical_list: D002135:Calcium-Binding Proteins; D018994:Myosin Light Chains; D000251:Adenosine Triphosphatases; D002118:Calcium