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Mutational Spectrum of the NKX2-5 Gene in Patients with Lone Atrial Fibrillation
- Source :
- International Journal of Medical Sciences
- Publication Year :
- 2014
- Publisher :
- Ivyspring International Publisher, 2014.
-
Abstract
- Atrial fibrillation (AF) is the most common form of sustained cardiac arrhythmia in humans and is responsible for substantial morbidity and mortality worldwide. Emerging evidence indicates that abnormal cardiovascular development is involved in the pathogenesis of AF. In this study, the coding exons and splice sites of the NKX2-5 gene, which encodes a homeodomain-containing transcription factor essential for cardiovascular genesis, were sequenced in 146 unrelated patients with lone AF as well as the available relatives of the mutation carriers. A total of 700 unrelated ethnically matched healthy individuals used as controls were genotyped. The disease-causing potential of the identified NKX2-5 variations was predicted by MutationTaster and PolyPhen-2. The functional characteristics of the mutant NKX2-5 proteins were analyzed using a dual-luciferase reporter assay system. As a result, two heterozygous NKX2-5 mutations, including a previously reported p.E21Q and a novel p.T180A mutation, were identified in two families with AF transmitted in an autosomal dominant pattern. The mutations co-segregated with AF in the families with complete penetrance. The detected substitutions, which altered the amino acids highly conserved evolutionarily across species, were absent in 700 control individuals and were both predicted to be causative. Functional analyses demonstrated that the NKX2-5 mutants were associated with significantly decreased transcriptional activity compared with their wild-type counterpart. The findings expand the spectrum of NKX2-5 mutations linked to AF and provide additional evidence that dysfunctional NKX2-5 may confer vulnerability to AF, suggesting the potential benefit for the early prophylaxis and personalized treatment of AF.
- Subjects :
- Adult
Male
medicine.medical_specialty
Mutation
Mutant
Biology
Bioinformatics
medicine.disease_cause
Homeobox protein Nkx-2.5
Pathogenesis
Structure-Activity Relationship
Exon
Asian People
Molecular genetics
medicine
Humans
Genetic Predisposition to Disease
Precision Medicine
Gene
Homeodomain Proteins
Genetics
General Medicine
Middle Aged
Atrial fibrillation
Penetrance
NKX2-5
Homeobox Protein Nkx-2.5
Female
RNA Splice Sites
Transcription factor
Sequence Alignment
Transcription Factors
Research Paper
Subjects
Details
- ISSN :
- 14491907
- Volume :
- 11
- Database :
- OpenAIRE
- Journal :
- International Journal of Medical Sciences
- Accession number :
- edsair.doi.dedup.....b3c8d77e4e1ab6deb5ecfebd3e6ddc0f