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

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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.
TidsskriftScandinavian Journal of Clinical & Laboratory Investigation
Udgave nummer8
Sider (fra-til)699-709
Antal sider11
StatusUdgivet - 2015

ID: 162647690