title: Actin mutations in hypertrophic and dilated cardiomyopathy cause inefficient protein folding and perturbed filament formation.
abstract: Hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) are the most common hereditary cardiac conditions. Both are frequent causes of sudden death and are often associated with an adverse disease course. Alpha-cardiac actin is one of the disease genes where different missense mutations have been found to cause either HCM or DCM. We have tested the hypothesis that the protein-folding pathway plays a role in disease development for two actin variants associated with DCM and six associated with HCM. Based on a cell-free coupled translation assay the actin variants could be graded by their tendency to associate with the chaperonin TCP-1 ring complex/chaperonin containing TCP-1 (TRiC/CCT) as well as their propensity to acquire their native conformation. Some variant proteins are completely stalled in a complex with TRiC and fail to fold into mature globular actin and some appear to fold as efficiently as the wild-type protein. A fraction of the translated polypeptide became ubiquitinated and detergent insoluble. Variant actin proteins overexpressed in mammalian cell lines fail to incorporate into actin filaments in a manner correlating with the degree of misfolding observed in the cell-free assay; ranging from incorporation comparable to wild-type actin to little or no incorporation. We propose that effects of mutations on folding and fiber assembly may play a role in the molecular disease mechanism.
authors.affiliation: Research Unit for Molecular Medicine, Aarhus University Hospital and Faculty of Health Sciences, Denmark. vang@ki.au.dk
authors.forename: Søren
authors.initials: S
authors.lastname: Vang
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Corydon
authors.forename: Anders D
authors.initials: AD
authors.lastname: Børglum
authors.forename: Melissa D
authors.initials: MD
authors.lastname: Scott
authors.forename: Judith
authors.initials: J
authors.lastname: Frydman
authors.forename: Jens
authors.initials: J
authors.lastname: Mogensen
authors.forename: Niels
authors.initials: N
authors.lastname: Gregersen
authors.forename: Peter
authors.initials: P
authors.lastname: Bross
mesh_terms: D008841:Actin Cytoskeleton / Q000737:chemistry / Q000378:metabolism; D000199:Actins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000235:genetics / Q000378:metabolism*; D002312:Cardiomyopathy, Hypertrophic / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D018833:Chaperonins / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D046912:Multiprotein Complexes / Q000737:chemistry / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D017510:Protein Folding; D012995:Solubility; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D000199:Actins; D046912:Multiprotein Complexes; D025801:Ubiquitin; D018833:Chaperonins