Loss-of-activity-mutation in the cardiac chloride-bicarbonate exchanger AE3 causes short QT syndrome
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Loss-of-activity-mutation in the cardiac chloride-bicarbonate exchanger AE3 causes short QT syndrome. / Thorsen, Kasper; Dam, Vibeke S.; Kjaer-Sorensen, Kasper; Pedersen, Lisbeth N.; Skeberdis, V. Arvydas; Jurevicius, Jonas; Treinys, Rimantas; Petersen, Ida M. B. S.; Nielsen, Morten S.; Oxvig, Claus; Morth, J. Preben; Matchkov, Vladimir V.; Aalkjaer, Christian; Bundgaard, Henning; Jensen, Henrik K.
In: Nature Communications, Vol. 8, 1696, 22.11.2017.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Loss-of-activity-mutation in the cardiac chloride-bicarbonate exchanger AE3 causes short QT syndrome
AU - Thorsen, Kasper
AU - Dam, Vibeke S.
AU - Kjaer-Sorensen, Kasper
AU - Pedersen, Lisbeth N.
AU - Skeberdis, V. Arvydas
AU - Jurevicius, Jonas
AU - Treinys, Rimantas
AU - Petersen, Ida M. B. S.
AU - Nielsen, Morten S.
AU - Oxvig, Claus
AU - Morth, J. Preben
AU - Matchkov, Vladimir V.
AU - Aalkjaer, Christian
AU - Bundgaard, Henning
AU - Jensen, Henrik K.
PY - 2017/11/22
Y1 - 2017/11/22
N2 - 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.
AB - 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.
U2 - 10.1038/s41467-017-01630-0
DO - 10.1038/s41467-017-01630-0
M3 - Journal article
C2 - 29167417
VL - 8
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 1696
ER -
ID: 187290760