title: The ubiquitin-proteasome system and nonsense-mediated mRNA decay in hypertrophic cardiomyopathy.
abstract: Cardiomyopathies represent an important cause of cardiovascular morbidity and mortality due to heart failure, arrhythmias, and sudden death. Most forms of hypertrophic cardiomyopathy (HCM) are familial with an autosomal-dominant mode of inheritance. Over the last 20 years, the genetic basis of the disease has been largely unravelled. HCM is considered as a sarcomeropathy involving mutations in sarcomeric proteins, most often beta-myosin heavy chain and cardiac myosin-binding protein C. 'Missense' mutations, more common in the former, are associated with dysfunctional proteins stably integrated into the sarcomere. 'Nonsense' and frameshift mutations, more common in the latter, are associated with low mRNA and protein levels derived from the diseased allele, leading to haploinsufficiency of the remaining healthy allele. The two quality control systems responsible for the removal of the affected mRNAs and proteins are the nonsense-mediated mRNA decay (NMD) and the ubiquitin-proteasome system (UPS), respectively. This review discusses clinical and genetic aspects of HCM and the role of NMD and UPS in the regulation of mutant proteins, evidence for impairment of UPS as a pathogenic factor, as well as potential therapies for HCM.
authors.affiliation: Institute of Experimental and Clinical Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany. l.carrier@uke.uni-hamburg.de
authors.forename: Lucie
authors.initials: L
authors.lastname: Carrier
authors.forename: Saskia
authors.initials: S
authors.lastname: Schlossarek
authors.forename: Monte S
authors.initials: MS
authors.lastname: Willis
authors.forename: Thomas
authors.initials: T
authors.lastname: Eschenhagen
mesh_terms: D000818:Animals; D006332:Cardiomegaly / Q000378:metabolism; D002312:Cardiomyopathy, Hypertrophic / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D006333:Heart Failure / Q000378:metabolism; D006801:Humans; D009154:Mutation; D018995:Myosin Heavy Chains / Q000235:genetics; D046988:Proteasome Endopeptidase Complex / Q000502:physiology*; D020871:RNA Stability; D025801:Ubiquitin / Q000378:metabolism*; D038203:alpha-Crystallin B Chain / Q000235:genetics; D000099163:Myosin Binding Protein C
chemical_list: D002352:Carrier Proteins; D018995:Myosin Heavy Chains; D046988:Proteasome Endopeptidase Complex; D025801:Ubiquitin; D038203:alpha-Crystallin B Chain; D000099163:Myosin Binding Protein C; C059215:CRYAB protein, human