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Nonsense mediated decay factor UPF3B is associated with cMyBP-C haploinsufficiency in hypertrophic cardiomyopathy

Valentin Burkart1, Kathrin Kowalski1, Alina Disch1

  • 1Institute for Molecular and Cell Physiology, Hannover Medical School, Hannover, Germany.

Journal of Molecular and Cellular Cardiology
|October 5, 2023
PubMed

Insights

Hypertrophic cardiomyopathy (HCM) is linked to myosin binding protein C (cMyBP-C) gene mutations. UPF3B-dependent nonsense-mediated decay (NMD) at the Z-disc explains cMyBP-C haploinsufficiency in HCM patients.

Area of Science:

  • Cardiovascular Genetics
  • Molecular Biology
  • Cell Biology

Background:

  • Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease, often caused by mutations in the MYBPC3 gene.
  • Many MYBPC3 mutations result in premature termination codons (PTCs), leading to reduced functional myosin binding protein C (cMyBP-C) and haploinsufficiency, a likely driver of HCM.
  • Distinguishing HCM-specific mechanisms from general hypertrophy is crucial, necessitating controls like aortic stenosis (AS).

Purpose of the Study:

  • To investigate the molecular mechanisms underlying cMyBP-C haploinsufficiency in HCM patients with MYBPC3 truncation mutations.
  • To determine if haploinsufficiency originates at the transcriptional, mRNA, or protein level.
  • To identify specific cellular pathways involved in HCM pathogenesis related to MYBPC3 mutations.

Main Methods:

  • Analysis of cardiac tissue from HCM patients with MYBPC3 truncation mutations (MYBPC3trunc) and AS patients, compared to donor controls.
  • Assessment of transcriptional activity, mRNA, and protein expression levels.
  • RNA-sequencing and Gene Set Enrichment Analysis (GSEA) to identify differentially expressed genes and pathways, focusing on nonsense-mediated decay (NMD) components.
  • Immunolocalization studies to determine the subcellular localization of NMD factors (UPF1, UPF2, UPF3B) within sarcomeres.

Main Results:

  • cMyBP-C haploinsufficiency in MYBPC3trunc HCM patients begins at the mRNA level, despite increased transcriptional activity due to hypertrophy.
  • GSEA revealed upregulation of NMD pathway components in MYBPC3trunc patients.
  • Up-frameshift protein UPF3B, an NMD regulator, was specifically upregulated in MYBPC3trunc patients but not in AS patients.
  • UPF3B, unlike UPF1 and UPF2, was localized to sarcomeric Z-discs, the site of sarcomeric protein translation.

Conclusions:

  • UPF3B-dependent nonsense-mediated decay (NMD) is a key mechanism establishing cMyBP-C haploinsufficiency in HCM.
  • This NMD process occurs during the initial translation round at the sarcomeric Z-disc.
  • These findings provide novel insights into the molecular pathogenesis of HCM driven by MYBPC3 mutations.

Keywords:
Hypertrophic cardiomyopathyNonsense mediated mRNA decayUPF3BcMyBP-C haploinsufficiency

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