TY - JOUR

T1 - Combined gating and trafficking defect in Kv11.1 manifests as a malignant long QT syndrome phenotype in a large Danish p.F29L founder family

AU - Kanters, Jørgen K.

AU - Skibsbye, Lasse

AU - Hedley, Paula L.

AU - Dembic, Maja

AU - Liang, Bo

AU - Hagen, Christian M.

AU - Eschen, Ole

AU - Grunnet, Morten

AU - Christiansen, Michael

AU - Jespersen, Thomas.

N1 - M1 - Copyright (C) 2015 American Chemical Society (ACS). All Rights Reserved. CAPLUS AN 2015:1819399(Journal)

PY - 2015

Y1 - 2015

N2 - Background: Congenital long QT syndrome (LQTS) is a hereditary cardiac channelopathy characterized by delayedventricular repolarization, syncope, torsades de pointes and sudden cardiac death. Thirty-three members of fi ve apparently‘ unrelated ’Danish families carry the KCNH2:c.87C A; p.F29L founder mutation. Methods and Results: Linkagedisequilibrium mapping with microsatellites around KCNH2 enabled us to estimate the age of the founder mutation to beapproximately 22 generations, corresponding to around 550 years. Neighbouring-Joining analysis disclosed one early andthree later nodes. The median QTc time of the carriers was 490 ms (range: 415 – 589 ms) and no difference was seenbetween the different branches of the family. The mutation is malignant with a penetrance of 73%. Ten F29L carriersreceived implantable defi brillators (ICDs) (median age at implant 20 years), and of those four individuals experienced eightappropriate shocks. Patch-clamp analysis in HEK 293 cells, performed at 34 °C disclosed a loss-of-function phenotype withfast deactivation, reduced steady-state inactivation current density and a positive voltage shift in inactivation. Western blottingof HEK 293 cells transfected with KCNH2:WT and KCNH2:c.87C A revealed a reduced fraction of fully glycosylatedhERG:p.F29L suggesting that this mutation results in defective traffi cking. Conclusion: The altered channel gatingkinetics in combination with defective traffi cking of mutated channels is expected to result in reduced repolarizing currentdensity and, thus, a LQTS phenotype.

AB - Background: Congenital long QT syndrome (LQTS) is a hereditary cardiac channelopathy characterized by delayedventricular repolarization, syncope, torsades de pointes and sudden cardiac death. Thirty-three members of fi ve apparently‘ unrelated ’Danish families carry the KCNH2:c.87C A; p.F29L founder mutation. Methods and Results: Linkagedisequilibrium mapping with microsatellites around KCNH2 enabled us to estimate the age of the founder mutation to beapproximately 22 generations, corresponding to around 550 years. Neighbouring-Joining analysis disclosed one early andthree later nodes. The median QTc time of the carriers was 490 ms (range: 415 – 589 ms) and no difference was seenbetween the different branches of the family. The mutation is malignant with a penetrance of 73%. Ten F29L carriersreceived implantable defi brillators (ICDs) (median age at implant 20 years), and of those four individuals experienced eightappropriate shocks. Patch-clamp analysis in HEK 293 cells, performed at 34 °C disclosed a loss-of-function phenotype withfast deactivation, reduced steady-state inactivation current density and a positive voltage shift in inactivation. Western blottingof HEK 293 cells transfected with KCNH2:WT and KCNH2:c.87C A revealed a reduced fraction of fully glycosylatedhERG:p.F29L suggesting that this mutation results in defective traffi cking. Conclusion: The altered channel gatingkinetics in combination with defective traffi cking of mutated channels is expected to result in reduced repolarizing currentdensity and, thus, a LQTS phenotype.

U2 - 10.3109/00365513.2015.1091090

DO - 10.3109/00365513.2015.1091090

M3 - Journal article

C2 - 26403377

VL - 75

SP - 699

EP - 709

JO - Scandinavian Journal of Clinical & Laboratory Investigation

JF - Scandinavian Journal of Clinical & Laboratory Investigation

SN - 0036-5513

IS - 8

ER -