title: Dilated cardiomyopathy mutations in δ-sarcoglycan exert a dominant-negative effect on cardiac myocyte mechanical stability.
abstract: Delta-sarcoglycan is a component of the sarcoglycan subcomplex within the dystrophin-glycoprotein complex located at the plasma membrane of muscle cells. While recessive mutations in δ-sarcoglycan cause limb girdle muscular dystrophy 2F, dominant mutations in δ-sarcoglycan have been linked to inherited dilated cardiomyopathy (DCM). The purpose of this study was to investigate functional cellular defects present in adult cardiac myocytes expressing mutant δ-sarcoglycans harboring the dominant inherited DCM mutations R71T or R97Q. This study demonstrates that DCM mutant δ-sarcoglycans can be stably expressed in adult rat cardiac myocytes and traffic similarly to wild-type δ-sarcoglycan to the plasma membrane, without perturbing assembly of the dystrophin-glycoprotein complex. However, expression of DCM mutant δ-sarcoglycan in adult rat cardiac myocytes is sufficient to alter cardiac myocyte plasma membrane stability in the presence of mechanical strain. Upon cyclical cell stretching, cardiac myocytes expressing mutant δ-sarcoglycan R97Q or R71T have increased cell-impermeant dye uptake and undergo contractures at greater frequencies than myocytes expressing normal δ-sarcoglycan. Additionally, the R71T mutation creates an ectopic N-linked glycosylation site that results in aberrant glycosylation of the extracellular domain of δ-sarcoglycan. Therefore, appropriate glycosylation of δ-sarcoglycan may also be necessary for proper δ-sarcoglycan function and overall dystrophin-glycoprotein complex function. These studies demonstrate that DCM mutations in δ-sarcoglycan can exert a dominant negative effect on dystrophin-glycoprotein complex function leading to myocardial mechanical instability that may underlie the pathogenesis of δ-sarcoglycan-associated DCM.
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan; and.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Campbell
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan; and.
authors.forename: Marc
authors.initials: M
authors.lastname: Witcher
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan; and.
authors.forename: Anoop
authors.initials: A
authors.lastname: Gopal
authors.affiliation: Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan; and Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, Michigan dmichele@umich.edu.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Michele
mesh_terms: D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism; D002463:Cell Membrane Permeability; D002478:Cells, Cultured; D005799:Genes, Dominant; D020022:Genetic Predisposition to Disease; D006031:Glycosylation; D006801:Humans; D040542:Mechanotransduction, Cellular; D009154:Mutation; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000378:metabolism*; D010641:Phenotype; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D017207:Rats, Sprague-Dawley; D049031:Sarcoglycans / Q000235:genetics* / Q000378:metabolism; D013314:Stress, Mechanical; D014162:Transfection
chemical_list: C526570:SGCD protein, human; D049031:Sarcoglycans
keywords: dilated cardiomyopathy; dye uptake; dystrophin-glycoprotein complex; mechanical strain; δ-sarcoglycan