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Protein haploinsufficiency drivers identify MYBPC3 variants that cause hypertrophic cardiomyopathy

Carmen Suay-Corredera1, Maria Rosaria Pricolo2, Elías Herrero-Galán1

  • 1Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain.

The Journal of Biological Chemistry
|June 7, 2021
PubMed

Insights

Genetic variants in MYBPC3 cause hypertrophic cardiomyopathy (HCM). Many variants lead to cardiac myosin-binding protein C (cMyBP-C) haploinsufficiency, a key mechanism in HCM development.

Area of Science:

  • Cardiovascular Genetics
  • Molecular Cardiology
  • Genetic Disease Mechanisms

Background:

  • Hypertrophic cardiomyopathy (HCM) is the most prevalent inherited cardiac condition.
  • MYBPC3 gene variants are the primary genetic cause of HCM.
  • The pathogenicity of numerous MYBPC3 variants remains undetermined due to limited understanding of HCM pathomechanisms.

Purpose of the Study:

  • To investigate the molecular mechanisms of 44 nontruncating MYBPC3 variants.
  • To determine the link between MYBPC3 variant effects and HCM pathogenicity.
  • To assess the impact of variants of uncertain significance on cMyBP-C function.

Main Methods:

  • Classified MYBPC3 variants using cosegregation and population genetics.
  • Assessed RNA splicing and protein stability for identified variants.
  • Evaluated the association of molecular phenotypes with HCM pathogenicity.

Main Results:

  • Approximately 50% of HCM-linked MYBPC3 variants impaired RNA splicing or protein stability, causing cMyBP-C haploinsufficiency.
  • These haploinsufficiency drivers demonstrated high specificity for HCM pathogenicity (100% and 94%).
  • 11% of variants classified as uncertain significance in ClinVar induced molecular phenotypes linked to HCM.

Conclusions:

  • cMyBP-C haploinsufficiency is a critical pathomechanism in HCM.
  • The study provides a strategy to classify variant pathogenicity for MYBPC3 and other genes.
  • This research clarifies the role of MYBPC3 variants in HCM and identifies potential therapeutic targets.

Keywords:
CDalternative splicingbioinformaticscardiac myosin-binding protein Chypertrophic cardiomyopathyminigeneprotein stabilityvariants of uncertain significance

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