A Novel Loss-of-Function Variant in the Chloride Ion Channel Gene Clcn2 Associates with Atrial Fibrillation
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A Novel Loss-of-Function Variant in the Chloride Ion Channel Gene Clcn2 Associates with Atrial Fibrillation. / Hansen, Thea Hyttel; Yan, Yannan; Ahlberg, Gustav; Vad, Oliver Bundgaard; Refsgaard, Lena; Dos Santos, Joana Larupa; Mutsaers, Nancy; Svendsen, Jesper Hastrup; Olesen, Morten Salling; Bentzen, Bo Hjorth; Schmitt, Nicole.
In: Scientific Reports, Vol. 10, No. 1, 1453, 29.01.2020.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - A Novel Loss-of-Function Variant in the Chloride Ion Channel Gene Clcn2 Associates with Atrial Fibrillation
AU - Hansen, Thea Hyttel
AU - Yan, Yannan
AU - Ahlberg, Gustav
AU - Vad, Oliver Bundgaard
AU - Refsgaard, Lena
AU - Dos Santos, Joana Larupa
AU - Mutsaers, Nancy
AU - Svendsen, Jesper Hastrup
AU - Olesen, Morten Salling
AU - Bentzen, Bo Hjorth
AU - Schmitt, Nicole
PY - 2020/1/29
Y1 - 2020/1/29
N2 - Atrial Fibrillation (AF) is the most common cardiac arrhythmia. Its pathogenesis is complex and poorly understood. Whole exome sequencing of Danish families with AF revealed a novel four nucleotide deletion c.1041_1044del in CLCN2 shared by affected individuals. We aimed to investigate the role of genetic variation of CLCN2 encoding the inwardly rectifying chloride channel ClC-2 as a risk factor for the development of familiar AF. The effect of the CLCN2 variant was evaluated by electrophysiological recordings on transiently transfected cells. We used quantitative PCR to assess CLCN2 mRNA expression levels in human atrial and ventricular tissue samples. The nucleotide deletion CLCN2 c.1041_1044del results in a frame-shift and premature stop codon. The truncated ClC-2 p.V347fs channel does not conduct current. Co-expression with wild-type ClC-2, imitating the heterozygote state of the patients, resulted in a 50% reduction in macroscopic current, suggesting an inability of truncated ClC-2 protein to form channel complexes with wild type channel subunits. Quantitative PCR experiments using human heart tissue from healthy donors demonstrated that CLCN2 is expressed across all four heart chambers. Our genetic and functional data points to a possible link between loss of ClC-2 function and an increased risk of developing AF.
AB - Atrial Fibrillation (AF) is the most common cardiac arrhythmia. Its pathogenesis is complex and poorly understood. Whole exome sequencing of Danish families with AF revealed a novel four nucleotide deletion c.1041_1044del in CLCN2 shared by affected individuals. We aimed to investigate the role of genetic variation of CLCN2 encoding the inwardly rectifying chloride channel ClC-2 as a risk factor for the development of familiar AF. The effect of the CLCN2 variant was evaluated by electrophysiological recordings on transiently transfected cells. We used quantitative PCR to assess CLCN2 mRNA expression levels in human atrial and ventricular tissue samples. The nucleotide deletion CLCN2 c.1041_1044del results in a frame-shift and premature stop codon. The truncated ClC-2 p.V347fs channel does not conduct current. Co-expression with wild-type ClC-2, imitating the heterozygote state of the patients, resulted in a 50% reduction in macroscopic current, suggesting an inability of truncated ClC-2 protein to form channel complexes with wild type channel subunits. Quantitative PCR experiments using human heart tissue from healthy donors demonstrated that CLCN2 is expressed across all four heart chambers. Our genetic and functional data points to a possible link between loss of ClC-2 function and an increased risk of developing AF.
U2 - 10.1038/s41598-020-58475-9
DO - 10.1038/s41598-020-58475-9
M3 - Journal article
C2 - 31996765
VL - 10
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 1453
ER -
ID: 238735731