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A Novel MEF2C Loss-of-Function Mutation Associated with Congenital Double Outlet Right Ventricle
- Source :
- Pediatric cardiology. 39(4)
- Publication Year :
- 2017
-
Abstract
- Congenital heart defect (CHD) represents the most prevalent birth defect, and accounts for substantial morbidity and mortality in humans. Aggregating evidence demonstrates the genetic basis for CHD. However, CHD is a heterogeneous disease, and the genetic determinants underlying CHD in most patients remain unknown. In the present study, a cohort of 186 unrelated cases with CHD and 300 unrelated control individuals were recruited. The coding exons and flanking introns of the MEF2C gene, which encodes a transcription factor crucial for proper cardiovascular development, were sequenced in all study participants. The functional effect of an identified MEF2C mutation was characterized using a dual-luciferase reporter assay system. As a result, a novel heterozygous MEF2C mutation, p.R15C, was detected in an index patient with congenital double outlet right ventricle (DORV) as well as ventricular septal defect. Analysis of the proband's pedigree showed that the mutation co-segregated with CHD with complete penetrance. The missense mutation, which changed the evolutionarily conserved amino acid, was absent in 300 control individuals. Functional deciphers revealed that the mutant MEF2C protein had a significantly decreased transcriptional activity. Furthermore, the mutation significantly reduced the synergistic activation between MEF2C and GATA4, another transcription factor linked to CHD. This study firstly associates MEF2C loss-of-function mutation with DORV in humans, which provides novel insight into the molecular pathogenesis of CHD, suggesting potential implications for genetic counseling and personalized treatment of CHD patients.
- Subjects :
- 0301 basic medicine
Proband
Heart Septal Defects, Ventricular
Male
Heterozygote
Adolescent
Genetic counseling
Mutation, Missense
Polymerase Chain Reaction
Cohort Studies
03 medical and health sciences
Exon
Asian People
Double outlet right ventricle
Genes, Reporter
medicine
Missense mutation
Humans
cardiovascular diseases
Child
Genetics
business.industry
GATA4
MEF2 Transcription Factors
Infant, Newborn
Infant
medicine.disease
Penetrance
Double Outlet Right Ventricle
Pedigree
030104 developmental biology
Child, Preschool
Pediatrics, Perinatology and Child Health
Mutation (genetic algorithm)
Mutagenesis, Site-Directed
Female
Cardiology and Cardiovascular Medicine
business
Subjects
Details
- ISSN :
- 14321971
- Volume :
- 39
- Issue :
- 4
- Database :
- OpenAIRE
- Journal :
- Pediatric cardiology
- Accession number :
- edsair.doi.dedup.....2a2a037c51d9ea8a6c34d45b8f5b4d98