PITX2C loss-of-function mutations responsible for idiopathic atrial fibrillation.
OBJECTIVE
This study aimed to identify novel PITX2c mutations responsible for idiopathic atrial fibrillation.


METHODS
A cohort of 210 unrelated patients with idiopathic atrial fibrillation and 200 unrelated, ethnically matched healthy individuals used as controls were recruited. The whole coding exons and splice junctions of the PITX2c gene, which encodes a paired-like homeobox transcription factor required for normal cardiovascular morphogenesis, were sequenced in 210 patients and 200 control subjects. The causative potentials of the identified mutations were automatically predicted by MutationTaster and PolyPhen-2. The functional characteristics of the PITX2c mutations were explored using a dual-luciferase reporter assay system.


RESULTS
Two novel heterozygous PITX2c mutations (p.Q105L and p.R122C) were identified in 2 of the 210 unrelated patients with idiopathic atrial fibrillation. These missense mutations were absent in the 400 control chromosomes and were both predicted to be pathogenic. Multiple alignments of PITX2c protein sequences across various species showed that the altered amino acids were highly evolutionarily conserved. A functional analysis demonstrated that the mutant PITX2c proteins were both associated with significantly reduced transcriptional activity compared with their wild-type counterparts.


CONCLUSIONS
The findings of this study associate PITX2c loss-of-function mutations with atrial fibrillation, supporting the hypothesis that dysfunctional PITX2c confers enhanced susceptibility to atrial fibrillation and suggesting potential implications for early prophylaxis and allele-specific therapy for this common arrhythmia.
Department of Cardiology and Cardiovascular Research, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China, Shanghai Jiao Tong University, Shanghai Chest Hospital, Department of Cardiology and Cardiovascular Research, Shanghai, China.
Xing-Biao
XB
Qiu
Department of Cardiology and Cardiovascular Research, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China, Shanghai Jiao Tong University, Shanghai Chest Hospital, Department of Cardiology and Cardiovascular Research, Shanghai, China.
Ying-Jia
YJ
Xu
Department of Cardiology and Cardiovascular Research, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China, Shanghai Jiao Tong University, Shanghai Chest Hospital, Department of Cardiology and Cardiovascular Research, Shanghai, China.
Ruo-Gu
RG
Li
Department of Cardiology and Cardiovascular Research, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China, Shanghai Jiao Tong University, Shanghai Chest Hospital, Department of Cardiology and Cardiovascular Research, Shanghai, China.
Lei
L
Xu
Department of Cardiology and Cardiovascular Research, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China, Shanghai Jiao Tong University, Shanghai Chest Hospital, Department of Cardiology and Cardiovascular Research, Shanghai, China.
Xu
X
Liu
Department of Cardiology and Cardiovascular Research, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China, Shanghai Jiao Tong University, Shanghai Chest Hospital, Department of Cardiology and Cardiovascular Research, Shanghai, China.
Wei-Yi
WY
Fang
Department of Cardiology and Cardiovascular Research, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China, Shanghai Jiao Tong University, Shanghai Chest Hospital, Department of Cardiology and Cardiovascular Research, Shanghai, China.
Yi-Qing
YQ
Yang
Department of Cardiology and Cardiovascular Research, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, China, Shanghai Jiao Tong University, Shanghai Chest Hospital, Department of Cardiology and Cardiovascular Research, Shanghai, China.
Xin-Kai
XK
Qu
D000368:Aged; D000595:Amino Acid Sequence; D001281:Atrial Fibrillation / Q000235:genetics*; D016022:Case-Control Studies; D015331:Cohort Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D049410:Luciferases, Renilla / Q000235:genetics; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D012307:Risk Factors; D016415:Sequence Alignment; D014157:Transcription Factors / Q000235:genetics*; D014158:Transcription, Genetic
D018398:Homeodomain Proteins; D014157:Transcription Factors; C433629:homeobox protein PITX3; D049410:Luciferases, Renilla