16 May 2005
Researchers in the US have identified a gene involved in a familial form of cardiovascular disease. A specific mutation in the MEF2A gene was shown to have a direct causal effect on the incidence of coronary artery disease (CAD) and heart attacks in a single large family with a history of CAD. Multiple risk factors for CAD and myocardial infarction (heart attack) have been identified, including obesity, hypertension and hypercholesterolemia, smoking and diabetes. Family history of the disease is also a known risk factor, but no specific associated genes have previously been identified, although chromosomal susceptibility loci have been reported from genetic studies. A paper in the latest edition of Science reports on genome-wide linkage analysis of thirteen members of a single family with an autosomal dominant pattern of CAD [Wang, L. et al. (2003) Science 302, 1578-1581]. Significant disease linkage was found with a locus on chromosome 15, a region that included a candidate causative gene, MEF2A, which encodes a transcription factor. Systematic DNA sequence analysis of the gene from each of the family members identified a specific 21 base-pair deletion in all affected individuals. This deletion was absent in unaffected members of the same family, and in over 100 control individuals with no evidence of CAD, suggesting that the deletion was the cause of CAD in the study family.
The seven amino acid deletion was found to prevent normal nuclear localisation of MEF2A, and to reduce the transcriptional activity of the protein to a third of wild-type levels. MEF2A is thought to play an important role in vascular endothelial cell development and function; the mutation may result in an abnormal vascular endothelium, which in turn could increase susceptibility to the formation of atherosclerotic plaques and hence to cardiovascular disease. Three additional large families with a history of CAD and MI were not found to show any genetic linkage between disease and the locus on chromosome 15, nor were any MEF2A mutations identified in 50 patients with non-familial cases of CAD and mycocardial infarction. The authors therefore propose that MEF2A mutations may be a rare cause of the disease, although large-scale association studies will be required to determine the actual prevalence of such mutations in general cardiovascular disease patient populations. They also suggest that the MEF2A signalling pathway and other genes regulating endothelial development and function may prove to be involved in the pathogenesis of CVD.
Comment: These results may prove to be highly significant to understanding genetic factors that underlie cardiovascular disease and the pathogenic process; however, they may also prove to have little or no relevance to the majority of familial or sporadic cases, as the gene deletion in question may be specific to the study family. Further studies will be required to determine whether MEF2A or additional genes related to vascular endothelial function are important for CVD in general.