Lack of MEF2A mutations in coronary artery disease

Abstract

Mutations in MEF2A have been implicated in an autosomal dominant form of coronary artery disease (adCAD1). In this study we sought to determine whether severe mutations in MEF2A might also explain sporadic cases of coronary artery disease (CAD). To do this, we resequenced the coding sequence and splice sites of MEF2A in approximately 300 patients with premature CAD and failed to find causative mutations in the CAD cohort. However, we did identify the 21-bp MEF2A coding sequence deletion originally implicated in adCAD1 in 1 of 300 elderly control subjects without CAD. Further screening of approximately 1,500 additional individuals without CAD revealed 2 more subjects with the MEF2A 21-bp deletion. Genotyping of 19 family members of the 3 probands with the 21-bp deletion in MEF2A revealed that the mutation did not cosegregate with early CAD. These studies support that MEF2A mutations are not a common cause of CAD in white people and argue strongly against a role for the MEF2A 21-bp deletion in autosomal dominant CAD.

Figure 1

Nucleotide and amino acid sequences of the repeat region in MEF2A. The shaded box marks the polyglutamine and -proline tandem repeats; the 21-bp deletion is boxed with dashed lines; arrows indicate the primers used for fragment-size analysis.

Figure 2

Sequence of the 21-bp deletion region of MEF2A. The PCR products from common and deletion alleles were separated by 3% agarose gel, purified, and cloned for sequencing analysis. The 21-bp deletion was identified in 3 independent control subjects. The 7 deleted amino acids are depicted with a dashed-line box. Haplotype analysis of all 3 subjects with the 21-bp deletion as well as approximately 370 control subjects indicates that this variant resides on a common haplotype, consistent with the deletion arising through a single ancestral founding event (data not shown).

Figure 3

MEF2A 21-bp deletion does not cosegregate with CAD in kindred no. 1 (Table 2). Individuals with premature CAD are indicated by filled squares (males) or circles (females). Unaffected individuals are indicated by open squares or circles. Normal males under the age of 50 years and normal females under the age of 55 years are shown in light gray, which indicates uncertain phenotype. Deceased individuals are indicated by a slash. The proband is indicated by an arrow. Genetic status: +/– indicates the presence of the 21-bp deletion of MEF2A (heterozygous); –/– indicates the absence of the deletion. Note that 3 elderly subjects with the 21-bp deletion do not have premature CAD, whereas the 2 subjects with premature CAD do not carry the deletion.