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A novel PITX2c loss‑of‑function mutation underlies lone atrial fibrillation.
- Source :
-
International journal of molecular medicine [Int J Mol Med] 2013 Oct; Vol. 32 (4), pp. 827-34. Date of Electronic Publication: 2013 Aug 02. - Publication Year :
- 2013
-
Abstract
- Atrial fibrillation (AF) is the most common form of sustained cardiac arrhythmia responsible for substantial morbidity and significantly increased mortality rates. A growing body of evidence documents the important role of genetic defects in the pathogenesis of AF. However, AF is a heterogeneous disease and the genetic determinants for AF in an overwhelming majority of patients remain unknown. In the present study, a cohort of 100 unrelated patients with lone AF and a total of 200 unrelated, ethnically matched healthy individuals used as controls, were recruited. The whole coding exons and splice junctions of the pituitary homeobox 2c (PITX2c) gene, which encodes a paired‑like homeobox transcription factor required for normal cardiovascular morphogenesis, were sequenced in the 100 patients and 200 control subjects. The causative potential of the identified mutation of PITX2c was predicted by MutationTaster and PolyPhen‑2. The functional characteristics of the PITX2c mutation were assayed using a dual‑luciferase reporter assay system. Based on the results, a novel heterozygous PITX2c mutation (p.T97A) was identified in a patient with AF. The missense mutation was absent in the 400 reference chromosomes and was automatically predicted to be disease‑causing. Multiple alignments of PITX2c protein sequences across species revealed that the altered amino acid was completely conserved evolutionarily. Functional analysis demonstrated that the mutant PITX2c protein was associated with significantly decreased transcriptional activity when compared with its wild‑type counterpart. The findings of the present study firstly link the PITX2c loss‑of‑function mutation to lone AF, and provide novel insight into the molecular mechanisms underlying AF, suggesting the potential implications for the early prophylaxis and allele‑specific therapy of this common type of arrhythmia.
- Subjects :
- Adult
Alleles
Amino Acid Sequence
Case-Control Studies
Cohort Studies
Exons
Female
Genetic Predisposition to Disease
Heterozygote
Homeodomain Proteins metabolism
Humans
Male
Middle Aged
Molecular Sequence Data
Mutation
Mutation, Missense
Phenotype
Sequence Alignment
Transcription Factors metabolism
Transcriptional Activation
Young Adult
Homeobox Protein PITX2
Atrial Fibrillation genetics
Atrial Fibrillation pathology
Homeodomain Proteins genetics
Transcription Factors genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1791-244X
- Volume :
- 32
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- International journal of molecular medicine
- Publication Type :
- Academic Journal
- Accession number :
- 23913021
- Full Text :
- https://doi.org/10.3892/ijmm.2013.1463