Related Experiment Video

Updated: Jun 21, 2026

Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
03:45

Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model

Published on: August 8, 2022

The ubiquitin-proteasome system and nonsense-mediated mRNA decay in hypertrophic cardiomyopathy

Lucie Carrier1, Saskia Schlossarek, Monte S Willis

  • 1Institute 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

Cardiovascular Research
|July 21, 2009
PubMed

Insights

Hypertrophic cardiomyopathy (HCM) involves genetic mutations affecting sarcomeric proteins. Quality control systems like nonsense-mediated mRNA decay (NMD) and ubiquitin-proteasome system (UPS) regulate mutant proteins, offering therapeutic targets.

Area of Science:

  • Cardiology
  • Genetics
  • Molecular Biology

Background:

  • Cardiomyopathies, particularly hypertrophic cardiomyopathy (HCM), are significant causes of heart failure, arrhythmias, and sudden death.
  • Most HCM cases are familial, inherited in an autosomal-dominant pattern, with genetics largely elucidated over the past two decades.
  • HCM is classified as a sarcomeropathy, typically caused by mutations in sarcomeric proteins like beta-myosin heavy chain and cardiac myosin-binding protein C.

Purpose of the Study:

  • To review the clinical and genetic aspects of hypertrophic cardiomyopathy (HCM).
  • To explore the roles of nonsense-mediated mRNA decay (NMD) and the ubiquitin-proteasome system (UPS) in regulating mutant proteins in HCM.
  • To discuss evidence implicating UPS impairment in pathogenesis and to consider potential therapeutic strategies for HCM.

Main Methods:

  • Review of existing literature on the genetic basis and pathophysiology of HCM.
  • Analysis of the mechanisms of nonsense-mediated mRNA decay (NMD) and ubiquitin-proteasome system (UPS) in relation to sarcomeric protein mutations.
  • Examination of evidence linking UPS dysfunction to HCM pathogenesis.

Main Results:

  • Missense mutations in beta-myosin heavy chain lead to dysfunctional sarcomeric proteins.
  • Nonsense and frameshift mutations in cardiac myosin-binding protein C result in haploinsufficiency via NMD and UPS.
  • Impairment of the ubiquitin-proteasome system (UPS) is suggested as a pathogenic factor in HCM.

Conclusions:

  • Understanding the genetic underpinnings and protein quality control mechanisms in HCM is crucial.
  • Nonsense-mediated mRNA decay (NMD) and ubiquitin-proteasome system (UPS) play key roles in HCM pathogenesis by managing mutant sarcomeric proteins.
  • Targeting NMD and UPS pathways presents potential therapeutic avenues for hypertrophic cardiomyopathy.

More Related Videos

Monitoring of Ubiquitin-proteasome Activity in Living Cells Using a Degron (dgn)-destabilized Green Fluorescent Protein (GFP)-based Reporter Protein10:25

Monitoring of Ubiquitin-proteasome Activity in Living Cells Using a Degron (dgn)-destabilized Green Fluorescent Protein (GFP)-based Reporter Protein

Published on: November 10, 2012

An Approach to Study Shape-Dependent Transcriptomics at a Single Cell Level06:02

An Approach to Study Shape-Dependent Transcriptomics at a Single Cell Level

Published on: November 2, 2020

Related Concept Videos

Nonsense-mediated mRNA Decay02:27

Nonsense-mediated mRNA Decay

The Upf proteins that carry out nonsense-mediated decay (NMD) are found in all eukaryotic organisms, including humans. Each protein has an individual role, but they need to work in collaboration. Upf1 is an ATP-dependent RNA helicase that unwinds the RNA helix. Because Upf1 can unwind any RNA, Upf2 and Upf3 are required to help Upf1 discriminate between nonsense and normal mRNAs.
Usually, Upf3 binds to an Exon Junction Complex (EJC) at mRNA splice sites. If a ribosome fully translates the mRNA,...
Nonsense-mediated mRNA Decay02:27

Nonsense-mediated mRNA Decay

The Upf proteins that carry out nonsense-mediated decay (NMD) are found in all eukaryotic organisms, including humans. Each protein has an individual role, but they need to work in collaboration. Upf1 is an ATP-dependent RNA helicase that unwinds the RNA helix. Because Upf1 can unwind any RNA, Upf2 and Upf3 are required to help Upf1 discriminate between nonsense and normal mRNAs.
Usually, Upf3 binds to an Exon Junction Complex (EJC) at mRNA splice sites. If a ribosome fully translates the mRNA,...
Nuclear Export of mRNA02:31

Nuclear Export of mRNA

Before mRNAs are exported to the cytoplasm, it is crucial to check each mRNA for structural and functional integrity. Eukaryotic cells use several different mechanisms, collectively known as mRNA surveillance, to look for irregularities in mRNAs. Irregular or aberrant mRNA are rapidly degraded by various enzymes. If a defective mRNA escapes the surveillance, it would be translated into a protein which would either be non-functional or not function properly. One of the primary irregularities in...
Cardiomyopathy III: Hypertrophic Cardiomyopathy01:29

Cardiomyopathy III: Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy, or HCM, is an autosomal dominant genetic disorder characterized by asymmetric left ventricular hypertrophy without ventricular dilation. It is more common in men and is typically diagnosed in young, athletic adults.EtiologyHCM is primarily genetic and is caused by mutations in genes encoding sarcomeric proteins. Researchers have identified over 1400 mutations across at least 11 different genes. Among these, the most frequently occurring mutations are found in the...
Export of Misfolded Proteins out of the ER01:32

Export of Misfolded Proteins out of the ER

After folding, the ER assesses the quality of secretory and membrane proteins. The correctly folded proteins are cleared by the calnexin cycle for transport to their final destination, while misfolded proteins are held back in the ER lumen. The ER chaperones attempt to unfold and refold the misfolded proteins but sometimes fail to achieve the correct native conformation. Such terminally misfolded proteins are then exported to the cytosol by ER-associated degradation or ERAD pathway for...
The Unfolded Protein Response01:37

The Unfolded Protein Response

The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...