PUBLICATION
Loss-of-activity-mutation in the cardiac chloride-bicarbonate exchanger AE3 causes short QT syndrome
- Authors
- Thorsen, K., Dam, V.S., Kjaer-Sorensen, K., Pedersen, L.N., Skeberdis, V.A., Jurevičius, J., Treinys, R., Petersen, I.M.B.S., Nielsen, M.S., Oxvig, C., Morth, J.P., Matchkov, V.V., Aalkjær, C., Bundgaard, H., Jensen, H.K.
- ID
- ZDB-PUB-171124-1
- Date
- 2017
- Source
- Nature communications 8: 1696 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Action Potentials/genetics
- Animals
- Antiporters/deficiency
- Antiporters/genetics*
- Antiporters/physiology
- Arrhythmias, Cardiac/etiology
- Arrhythmias, Cardiac/genetics*
- Arrhythmias, Cardiac/physiopathology
- Cell Membrane/physiology
- Chloride-Bicarbonate Antiporters/deficiency
- Chloride-Bicarbonate Antiporters/genetics
- Chloride-Bicarbonate Antiporters/physiology
- Disease Models, Animal
- Electrocardiography
- Exome Sequencing
- Female
- Gene Knockdown Techniques
- Genetic Predisposition to Disease
- HEK293 Cells
- Heart/physiopathology
- Heterozygote
- Humans
- Hydrogen-Ion Concentration
- Loss of Function Mutation*
- Male
- Mutation, Missense
- Pedigree
- Zebrafish/genetics
- Zebrafish/physiology
- Zebrafish Proteins/deficiency
- Zebrafish Proteins/genetics
- Zebrafish Proteins/physiology
- PubMed
- 29167417 Full text @ Nat. Commun.
Citation
Thorsen, K., Dam, V.S., Kjaer-Sorensen, K., Pedersen, L.N., Skeberdis, V.A., Jurevičius, J., Treinys, R., Petersen, I.M.B.S., Nielsen, M.S., Oxvig, C., Morth, J.P., Matchkov, V.V., Aalkjær, C., Bundgaard, H., Jensen, H.K. (2017) Loss-of-activity-mutation in the cardiac chloride-bicarbonate exchanger AE3 causes short QT syndrome. Nature communications. 8:1696.
Abstract
Patients with short QT syndrome (SQTS) may present with syncope, ventricular fibrillation or sudden cardiac death. Six SQTS susceptibility genes, encoding cation channels, explain <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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping