Back to Search
Start Over
Prevalence and Spectrum of NKX2-5 Mutations Associated With Sporadic Adult-Onset Dilated Cardiomyopathy
- Source :
- International Heart Journal. 58:521-529
- Publication Year :
- 2017
- Publisher :
- International Heart Journal (Japanese Heart Journal), 2017.
-
Abstract
- Dilated cardiomyopathy (DCM), the most common form of primary myocardial disease, is a leading cause of congestive heart failure and the most common indication for heart transplantation. Recently, NKX2-5 mutations have been involved in the pathogenesis of familial DCM. However, the prevalence and spectrum of NKX2-5 mutations associated with sporadic DCM remain to be evaluated. In this study, the coding regions and flanking introns of the NKX2-5 gene, which encodes a cardiac transcription factor pivotal for cardiac development and structural remodeling, were sequenced in 210 unrelated patients with sporadic adult-onset DCM. A total of 300 unrelated healthy individuals used as controls were also genotyped for NKX2-5. The functional effect of the mutant NKX2-5 was investigated using a dual-luciferase reporter assay system. As a result, two novel heterozygous NKX2-5 mutations, p.R139W and p.E167X, were identified in 2 unrelated patients with sporadic adult-onset DCM, with a mutational prevalence of approximately 0.95%. The mutations were absent in 600 referential chromosomes and the altered amino acids were completely conserved evolutionarily across species. Functional assays revealed that the NKX2-5 mutants were associated with significantly reduced transcriptional activity. Furthermore, the mutations abrogated the synergistic activation between NKX2-5 and GATA4 as well as TBX20, two other cardiac key transcription factors that have been causally linked to adult-onset DCM. This study is the first to associate NKX2-5 loss-of-function mutations with enhanced susceptibility to sporadic DCM, which provides novel insight into the molecular etiology underpinning DCM, and suggests the potential implications for the genetic counseling and personalized treatment of the DCM patients.
- Subjects :
- Cardiomyopathy, Dilated
Male
0301 basic medicine
China
Genotype
TBX20
DNA Mutational Analysis
030204 cardiovascular system & hematology
medicine.disease_cause
Polymerase Chain Reaction
Pathogenesis
03 medical and health sciences
0302 clinical medicine
Genes, Reporter
Prevalence
medicine
Humans
cardiovascular diseases
Age of Onset
Gene
Transcription factor
Genetics
Mutation
business.industry
GATA4
Dilated cardiomyopathy
DNA
General Medicine
Middle Aged
medicine.disease
Pedigree
030104 developmental biology
Heart failure
Homeobox Protein Nkx-2.5
cardiovascular system
Female
Cardiology and Cardiovascular Medicine
business
Follow-Up Studies
Subjects
Details
- ISSN :
- 13493299 and 13492365
- Volume :
- 58
- Database :
- OpenAIRE
- Journal :
- International Heart Journal
- Accession number :
- edsair.doi.dedup.....5ffccc5fd0613509429e9daa927b663f