A Novel PITX2c Gain-of-Function Mutation, p.Met207Val, in Patients With Familial Atrial Fibrillation

Am J Cardiol. 2019 Mar 1;123(5):787-793. doi: 10.1016/j.amjcard.2018.11.047. Epub 2018 Dec 3.


Genome-wide studies have associated several genetic variants upstream of PITX2 on chromosome 4q25 with atrial fibrillation (AF), suggesting a potential role of PITX2 in AF. Our study aimed at identifying rare coding variants in PITX2 predisposing to AF. The Polymerase chain reaction sequencing of PITX2c was performed in 60 unrelated patients with idiopathic AF. The p.Met207Val variant was identified in 1 of 60 French patients with early onset AF and in none of 389 French referents. This variant, located in the inhibitory domain 1 distal to the homeodomain, was evaluated by the software MutationTaster as a disease-causing mutation with a probability of 0.999. Reporter gene assays demonstrated that p.Met207Val caused a 3.1-fold increase in transactivation activity of PITX2c in HeLa cells in comparison with its wild-type counterpart. When the variant was coexpressed with wild-type PITX2c in the HL-1 immortalized mouse atrial cell line, this gain-of-function caused an increase in the mRNA level of KCNH2 (2.6-fold), SCN1B (1.9-fold), GJA5 (3.1-fold), GJA1 (2.1-fold), and KCNQ1 in the homozygous form (1.8-fold). These genes encode for the IKr channel α subunit, the β-1 Na+ channel subunit, connexin 40, connexin 43 and the IKs channel α subunit, respectively. These conditions may contribute to the propensity to AF found in patients carrying the p.Met207Val variant. In conclusion, the present report is the first to associate a gain-of-function mutation of PITX2c with increased vulnerability to AF, therefore, restoration of normal PITX2c function may be a potential therapeutic target in AF patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Atrial Fibrillation / genetics*
  • Atrial Fibrillation / metabolism
  • DNA / genetics*
  • DNA Mutational Analysis
  • Female
  • Gain of Function Mutation*
  • Gene Frequency
  • Genotype
  • Homeobox Protein PITX2
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism
  • Humans
  • Male
  • Middle Aged
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / pathology
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism


  • Homeodomain Proteins
  • Transcription Factors
  • DNA