Human Molecular Genetics Advance Access originally published online on October 20, 2004
Human Molecular Genetics 2004 13(24):3181-3188; doi:10.1093/hmg/ddh329
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Human Molecular Genetics, Vol. 13, No. 24 © Oxford University Press 2004; all rights reserved
Transcription factor MEF2A mutations in patients with coronary artery disease
1Department of Molecular Cardiology, Lerner Research Institute, 2Center for Cardiovascular Genetics, Department of Cardiovascular Medicine, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA and 3Department of Biological, Geological and Environmental Sciences, Cleveland State University, Cleveland, OH 44115, USA
Received August 25, 2004; Accepted October 11, 2004
Coronary artery disease (CAD), including its most serious complication myocardial infraction (MI), is the leading cause of death in the US and developed countries. We recently discovered that a seven-amino acid deletion in MEF2A, a transcription factor with a high level of expression in the endothelium of coronary arteries, co-segregates with CAD/MI in one family, and it suppresses transcription activation activity of MEF2A by a dominant-negative mechanism. In this study, we used single-strand conformation polymorphism and DNA sequence analyses to identify mutations in MEF2A in 207 independent CAD/MI patients and 191 controls with normal angiograms. We identified three novel mutations in exon 7 of MEF2A in four of 207 CAD/MI patients (1.93%). No mutations were detected in the 191 controls. The mutations identified here include N263S identified in two independent CAD patients, P279L in one patient and his father with the diagnosis of CAD and G283D in one patient. These mutations are clustered within or close to the major transcriptional activation domain of MEF2A. They significantly reduce the transcriptional activation activity of MEF2A and act by a loss-of-function mechanism. The gene carriers with loss-of-function mutations appear to be associated with less severe CAD. These results suggest that CAD/MI can result from a spectrum of MEF2A transcription dysfunctions ranging from loss-of-function to dominant-negative suppression and that a significant percent of the CAD/MI population (1.93%) may carry mutations in MEF2A, although further definition of the prevalence of MEF2A mutations is warranted.
* To whom correspondence should be addressed at: Center for Molecular Genetics/ND4-38, The Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. Tel: +1 2164450570; Fax: +1 2164442682; Email: wangq2{at}ccf.org
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