Mutation of MEF2A in an inherited disorder with features of coronary artery disease.
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.
Wang
Lejin
L
Center 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.
Fan
Chun
C
Topol
Sarah E
SE
Topol
Eric J
EJ
Wang
Qing
Q
D000368:Aged; D000595:Amino Acid Sequence; D000818:Animals; D001158:Arteries / Q000378:metabolism; D001483:Base Sequence; D002467:Cell Nucleus / Q000378:metabolism; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics; D003324:Coronary Artery Disease / Q000235:genetics* / Q000378:metabolism; D003331:Coronary Vessels / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D019281:Dimerization; D004730:Endothelium, Vascular / Q000378:metabolism; D050981:Erythroid-Specific DNA-Binding Factors; D005260:Female; D005455:Fluorescent Antibody Technique; D050982:GATA1 Transcription Factor; D015870:Gene Expression; D005799:Genes, Dominant; D008040:Genetic Linkage; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D006801:Humans; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009130:Muscle, Smooth / Q000166:cytology / Q000378:metabolism; D009203:Myocardial Infarction / Q000235:genetics* / Q000378:metabolism; D018006:Myogenic Regulatory Factors; D010375:Pedigree; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D051381:Rats; D012307:Risk Factors; D017384:Sequence Deletion; D015398:Signal Transduction; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation
D004268:DNA-Binding Proteins; D050981:Erythroid-Specific DNA-Binding Factors; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; C494690:Gata1 protein, rat; D005819:Genetic Markers; D026161:MADS Domain Proteins; D064326:MEF2 Transcription Factors; C578035:MEF2A protein, human; D018006:Myogenic Regulatory Factors; D014157:Transcription Factors