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Mutation of MEF2A in an inherited disorder with features of coronary artery disease

Lejin Wang1, Chun Fan, Sarah E Topol

  • 1Center for Cardiovascular Genetics, Department of Cardiovascular Medicine, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195, USA.

Science (New York, N.Y.)
|December 3, 2003
PubMed

Insights

Genetic factors in coronary artery disease (CAD) and myocardial infarction (MI) are unclear. A MEF2A gene deletion causes familial CAD/MI by disrupting protein function and implicating the MEF2A pathway in disease development.

Area of Science:

  • Genetics
  • Cardiovascular Disease
  • Molecular Biology

Background:

  • The genetic underpinnings of coronary artery disease (CAD) and myocardial infarction (MI) pathogenesis are not fully understood.
  • Identifying early genetic triggers is crucial for understanding disease development.

Purpose of the Study:

  • To identify the genetic cause of an autosomal dominant form of CAD/MI (adCAD1).
  • To elucidate the molecular mechanism by which the identified genetic defect contributes to CAD/MI pathogenesis.
  • To investigate the role of the MEF2A signaling pathway in cardiovascular disease.

Main Methods:

  • Described an autosomal dominant form of CAD/MI (adCAD1).
  • Utilized genetic analysis to identify a deletion in the transcription factor MEF2A.
  • Investigated the functional consequences of the MEF2A deletion on protein localization and transcriptional activity.
  • Examined MEF2A expression in coronary artery endothelium.

Main Results:

  • Identified a seven-amino acid deletion in the MEF2A gene as the cause of adCAD1.
  • The MEF2A deletion impairs nuclear localization and reduces transcriptional activation.
  • Demonstrated a dominant-negative mechanism abolishing synergistic activation with GATA-1.
  • Confirmed strong MEF2A expression in the endothelium of coronary arteries.

Conclusions:

  • Identified MEF2A as a pathogenic gene for familial CAD/MI.
  • The MEF2A signaling pathway is implicated in the pathogenesis of CAD and MI.
  • This finding provides new insights into the genetic basis of cardiovascular diseases.

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