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 -