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

BACKGROUND: Congenital long QT syndrome (LQTS) is a hereditary cardiac channelopathy characterized by delayed ventricular repolarization, syncope, torsades de pointes and sudden cardiac death. Thirty-three members of five apparently 'unrelated' Danish families carry the KCNH2:c.87C> A; p.F29L founder mutation.METHODS AND RESULTS: Linkage disequilibrium mapping with microsatellites around KCNH2 enabled us to estimate the age of the founder mutation to be approximately 22 generations, corresponding to around 550 years. Neighbouring-Joining analysis disclosed one early and three later nodes. The median QTc time of the carriers was 490 ms (range: 415-589 ms) and no difference was seen between the different branches of the family. The mutation is malignant with a penetrance of 73%. Ten F29L carriers received implantable defibrillators (ICDs) (median age at implant 20 years), and of those four individuals experienced eight appropriate shocks. Patch-clamp analysis in HEK 293 cells, performed at 34°C disclosed a loss-of-function phenotype with fast deactivation, reduced steady-state inactivation current density and a positive voltage shift in inactivation. Western blotting of HEK 293 cells transfected with KCNH2:WT and KCNH2:c.87C> A revealed a reduced fraction of fully glycosylated hERG:p.F29L suggesting that this mutation results in defective trafficking.CONCLUSION: The altered channel gating kinetics in combination with defective trafficking of mutated channels is expected to result in reduced repolarizing current density and, thus, a LQTS phenotype.