Mutation of MEF2A in an Inherited Disorder with Features of Coronary Artery Disease

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.

Toward transcriptional therapies for the failing heart: chemical screens to modulate genes

“…Indeed, ablation of MEF2 in the heart can lead to dilated cardiomyopathy in mice and has been linked to increased risk of myocardial infarction in humans (46,47). These phenotypes may be related to the ability of MEF2 to regulate expression of the PPARγ coactivator-1α (PGC-1) transcription factor, a master regulator of mitochondrial biogenesis (48).…”

The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke

“…Case-control association studies have identified several proinflammatory genes with variants that are associated with either an increased risk of myocardial infarction or a protective effect [7][8][9] . Four genome-wide scans in families with myocardial infarction have yielded several loci with formidable linkage peaks, but the gene(s) underlying these loci have not yet been identified [10][11][12][13][14] . In addition, one large pedigree study identified a deletion mutation of a transcription factor gene, MEF2A, with autosomal dominant transmission 14 .…”

“…Four genome-wide scans in families with myocardial infarction have yielded several loci with formidable linkage peaks, but the gene(s) underlying these loci have not yet been identified [10][11][12][13][14] . In addition, one large pedigree study identified a deletion mutation of a transcription factor gene, MEF2A, with autosomal dominant transmission 14 . This is an interesting cause of myocardial infarction, but the prevalence of this or other mutations in MEF2A outside this family remains to be determined.…”

Cardiovascular Genetic Medicine: The Genetics of Coronary Heart Disease

“…One study by Wang et al examined a family cohort with a high prevalence of myocardial infarction and found linkage for a region on chromosome 15. [8] The putative candidate gene in this chromosomal region was identified as myocyte enhancer factor 2A (mef2a). In another linkage study, Broeckel et al studied a group of 513 unrelated families in which there was at least one member with a documented myocardial infarction.…”