Loss-of-activity-mutation in the cardiac chloride-bicarbonate exchanger AE3 causes short QT syndrome

Patients with short QT syndrome (SQTS) may present with syncope, ventricular fibrillation or sudden cardiac death. Six SQTS susceptibility genes, encoding cation channels, explain less than 25% of SQTS cases. Here we identify a missense mutation in the anion exchanger (AE3)-encoding SLC4A3 gene in two unrelated families with SQTS. The mutation causes reduced surface expression of AE3 and reduced membrane bicarbonate transport. Slc4a3 knockdown in zebrafish causes increased cardiac pHi, short QTc, and reduced systolic duration, which is rescued by wildtype but not mutated SLC4A3. Mechanistic analyses suggest that an increase in pHi and decrease in [Cl-]i shortened the action potential duration. However, other mechanisms may also play a role. Altered anion transport represents a mechanism for development of arrhythmia and may provide new therapeutic possibilities.

Type: Other
Archiver: European Genome-Phenome Archive (EGA)

1 Dataset 1 Publication

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Dataset ID	Description	Technology	Samples
EGAD00001003745	Exome sequencing fastq files from 6 mutation carriers and 5 non-carriers from 2 families. One µg DNA was used for library preparation using the TruSeq DNA LT Sample Prep Kit v2 according to the manufacturer’s instructions (Illumina). Hybridization was performed using Nimblegen SeqCap EZ Exome v3 (Roche) and Paired-end Sequencing (2x100 bp) on the Illumina HiSeq 2000 with TruSeq v3 chemistry (Illumina).	Illumina HiSeq 2000	11

Publications	Citations
Loss-of-activity-mutation in the cardiac chloride-bicarbonate exchanger AE3 causes short QT syndrome. Thorsen K, Dam VS, Kjaer-Sorensen K, Pedersen LN, Skeberdis VA, Jurevičius J, Treinys R, Petersen IMBS, Nielsen MS, Oxvig C, Morth JP, Matchkov VV, Aalkjær C, Bundgaard H, Jensen HK. Nat Commun 8: 2017 1696	45