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A novel PITX2c loss-of-function mutation associated with familial atrial fibrillation
- Source :
- European journal of medical genetics. 57(1)
- Publication Year :
- 2013
-
Abstract
- Atrial fibrillation (AF) represents the most prevalent form of sustained cardiac arrhythmia and contributes substantially to cardiovascular morbidity and mortality. Aggregating evidence demonstrates that genetic risk factors play an important role in the pathogenesis of AF. However, AF is a genetically heterogeneous disease and the genetic defects responsible for AF in an overwhelming majority of patients remain unclear. In the present study, the whole coding region and splice junction sites of the PITX2c gene, which encodes a paired-like homeobox transcription factor essential for normal cardiovascular development, were sequenced in 160 unrelated patients with lone AF, and a novel heterozygous mutation, c.349C > T equivalent to p.P117S, was identified in a patient with positive family history of AF. The missense mutation, which co-segregated with AF in the family with complete penetrance and was absent in 700 unrelated ethnically matched healthy individuals, altered the amino acid completely conserved evolutionarily across species and was predicted to be pathogenic by MutationTaster and PolyPhen-2. Biological assays revealed that the mutant PITX2c protein was associated with significantly decreased transcriptional activity when compared with its wild-type counterpart. The findings implicate PITX2c loss-of-function mutation in familial AF for the first time, providing novel insight into the molecular pathology of AF.
- Subjects :
- Adult
Male
Mutant
DNA Mutational Analysis
Molecular Sequence Data
Mutation, Missense
Biology
medicine.disease_cause
Bioinformatics
Pathogenesis
Atrial Fibrillation
Genetics
medicine
Missense mutation
Humans
Genetic Predisposition to Disease
Amino Acid Sequence
Gene
Genetics (clinical)
Genetic Association Studies
Homeodomain Proteins
Mutation
Base Sequence
Genetic heterogeneity
General Medicine
Middle Aged
medicine.disease
Penetrance
Pedigree
Case-Control Studies
Female
Familial atrial fibrillation
Transcription Factors
Subjects
Details
- ISSN :
- 18780849
- Volume :
- 57
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- European journal of medical genetics
- Accession number :
- edsair.doi.dedup.....52d5a333ac660a51fe8f18f58e3b788e