title: A novel PITX2c loss-of-function mutation associated with familial atrial fibrillation.
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.
authors: Department of Cardiology, East Hospital, Tongji University School of Medicine, 150 Jimo Road, Shanghai 200120, China.
authors: Jun
authors: J
authors: Wang
authors: Department of Cardiology, East Hospital, Tongji University School of Medicine, 150 Jimo Road, Shanghai 200120, China. Electronic address: zhangdaifu69@sina.cn.
authors: Dai-Fu
authors: DF
authors: Zhang
authors: Department of Cardiology, Jing-An District Central Hospital, 259 Xikang Road, Shanghai 200040, China.
authors: Yu-Min
authors: YM
authors: Sun
authors: Department of Cardiology, Cardiovascular Research Laboratory and Central Laboratory, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai 200030, China. Electronic address: yang99yang66@hotmail.com.
authors: Yi-Qing
authors: YQ
authors: Yang
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D001281:Atrial Fibrillation / Q000235:genetics*; D001483:Base Sequence; D016022:Case-Control Studies; D004252:DNA Mutational Analysis; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D014157:Transcription Factors / Q000235:genetics*; D000097577:Homeobox Protein PITX2
chemical_list: D018398:Homeodomain Proteins; D014157:Transcription Factors; D000097577:Homeobox Protein PITX2
keywords: Atrial fibrillation; Genetics; PITX2c; Reporter gene; Transcriptional factor