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

Science. 2003 Nov 28;302(5650):1578-81. doi: 10.1126/science.1088477.

Abstract

The early genetic pathway(s) triggering the pathogenesis of coronary artery disease (CAD) and myocardial infarction (MI) remain largely unknown. Here, we describe an autosomal dominant form of CAD/MI (adCAD1) that is caused by the deletion of seven amino acids in transcription factor MEF2A. The deletion disrupts nuclear localization of MEF2A, reduces MEF2A-mediated transcription activation, and abolishes synergistic activation by MEF2A and by the transcription factor GATA-1 through a dominant-negative mechanism. The MEF2A protein demonstrates strong expression in the endothelium of coronary arteries. These results identify a pathogenic gene for a familial vascular disease with features of CAD and implicate the MEF2A signaling pathway in the pathogenesis of CAD/MI.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aged
  • Amino Acid Sequence
  • Animals
  • Arteries / metabolism
  • Base Sequence
  • Cell Nucleus / metabolism
  • Chromosomes, Human, Pair 15 / genetics
  • Coronary Artery Disease / genetics*
  • Coronary Artery Disease / metabolism
  • Coronary Vessels / metabolism
  • DNA-Binding Proteins / chemistry
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Dimerization
  • Endothelium, Vascular / metabolism
  • Erythroid-Specific DNA-Binding Factors
  • Female
  • Fluorescent Antibody Technique
  • GATA1 Transcription Factor
  • Gene Expression
  • Genes, Dominant
  • Genetic Linkage
  • Genetic Markers
  • Genetic Predisposition to Disease
  • Humans
  • MADS Domain Proteins
  • MEF2 Transcription Factors
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Muscle, Smooth / cytology
  • Muscle, Smooth / metabolism
  • Myocardial Infarction / genetics*
  • Myocardial Infarction / metabolism
  • Myogenic Regulatory Factors
  • Pedigree
  • Protein Binding
  • Protein Conformation
  • Protein Structure, Tertiary
  • Protein Transport
  • Rats
  • Risk Factors
  • Sequence Deletion*
  • Signal Transduction
  • Transcription Factors / chemistry
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Transcriptional Activation

Substances

  • DNA-Binding Proteins
  • Erythroid-Specific DNA-Binding Factors
  • GATA1 Transcription Factor
  • GATA1 protein, human
  • Gata1 protein, rat
  • Genetic Markers
  • MADS Domain Proteins
  • MEF2 Transcription Factors
  • MEF2A protein, human
  • Myogenic Regulatory Factors
  • Transcription Factors