MEF2C loss-of-function mutation associated with familial dilated cardiomyopathy

Background:The MADS-box transcription factor myocyte enhancer factor 2C (MEF2C) is required for the cardiac development and postnatal adaptation and in mice-targeted disruption of theMEF2Cgene results in dilated cardiomyopathy (DCM). However, in humans, the association ofMEF2Cvariation with DCM remains to be investigated.Methods:The coding regions and splicing boundaries of theMEF2Cgene were sequenced in 172 unrelated patients with idiopathic DCM. The available close relatives of the index patient harboring an identifiedMEF2Cmutation and 300 unrelated, ethnically matched healthy individuals used as controls were genotyped forMEF2C. The functional effect of the mutant MEF2C protein was characterized in contrast to its wild-type counterpart by using a dual-luciferase reporter assay system.Results:A novel heterozygous MEF2C mutation, p.Y157X, was detected in an index patient with adult-onset DCM. Genetic screen of the mutation carrier’s family members revealed that the mutation co-segregated with DCM, which was transmitted as an autosomal dominant trait with complete penetrance. The non-sense mutation was absent in 300 control individuals. Functional analyses unveiled that the mutant MEF2C protein had no transcriptional activity. Furthermore, the mutation abolished the synergistic transactivation between MEF2C and GATA4 as well as HAND1, two other transcription factors that have been associated with DCM.Conclusions:This study indicatesMEF2Cas a new gene responsible for human DCM, which provides novel insight into the mechanism underpinning DCM, suggesting potential implications for development of innovative prophylactic and therapeutic strategies for DCM, the most prevalent form of primary myocardial disease.