Cardiovascular Research Advance Access first published online on July 17, 2009
This version [Corrected Proof] published online on August 10, 2009
Cardiovascular Research, doi:10.1093/cvr/cvp247
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Ubiquitin–proteasome system and nonsense-mediated mRNA decay in hypertrophic cardiomyopathy
1 Institute of Experimental and Clinical Pharmacology and Toxicology, Cardiovascular Research Center, University Medical Center Hamburg-Eppendorf, Martinistraße 52, D-20246 Hamburg, Germany
2 Inserm, U974, Institut de Myologie, Paris F-75013, France
3 Université Pierre et Marie Curie-Paris 6, UMR-S974, CNRS, UMR7215, Institut de Myologie, IFR14, Paris F-75013, France
4 Carolina Cardiovascular Biology Center, University of North Carolina, Chapel Hill, NC, USA
5 Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA
* Corresponding author. Tel: +49 40 7410 57208, Fax: +49 40 7410 55925, Email: l.carrier{at}uke.uni-hamburg.de
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 β-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.
KEYWORDS Hypertrophy; Cardiomyopathy; Ubiquitin–proteasome system; Nonsense-mediated mRNA decay
Time for primary review: 32 days
This article is part of the Spotlight Issue on: The Role of the Ubiquitin-Proteasome Pathway in Cardiovascular Disease