A new C-terminal hERG mutation A915fs+47X associated with symptomatic LQT2 and auditory-trigger syncope.
BACKGROUND
A novel mutation of hERG (A915fs+47X) was discovered in a 32-year-old woman with torsades de pointes, long QTc interval (515 ms), and syncope upon auditory trigger.


OBJECTIVE
We explored whether the properties of this mutation could explain the pathology.


METHODS
Whole-cell A915fs+47X (del) and wild-type (WT) currents were recorded in transiently transfected COS7 cells or Xenopus oocytes. Western blots and sedimentation analysis of del/WT hERG were used to analyze protein expression, assembly, and trafficking.


RESULTS
The tail current density at -40 mV after a 2-s depolarization to +40 mV in COS7 cells expressing del was 36% of that for WT. Inactivation was 1.9-fold to 2.8-fold faster in del versus WT between -60 and +60 mV. In the range -60 to -10 mV, we found that a nondeactivating fraction of current was increased in del at the expense of a rapidly deactivating fraction, with a slowly deactivating fraction being unchanged. In Xenopus oocytes, expression of del alone produced 38% of WT currents, whereas coexpression of 1/2 WT + 1/2 del produced 49.8%. Furthermore, the expression of del protein at the cell surface was reduced by about 50%. This suggests that a partial trafficking defect of del contributes to the reduction in del current densities and to the dominant negative effect when coexpressed with WT. In model simulations, the mutation causes a 10% prolongation of action potential duration.


CONCLUSIONS
Decreased current levels caused by a trafficking defect may explain the long QT syndrome observed in our patient.
Christé
Georges
G
INSERM, ADR Lyon, Lyon, F-69003 France. georges.christe@inserm.fr
Thériault
Olivier
O
Chahine
Mohamed
M
Millat
Gilles
G
Rodriguez-Lafrasse
Claire
C
Rousson
Robert
R
Deschênes
Isabelle
I
Ficker
Eckhard
E
Chevalier
Philippe
P
D000328:Adult; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000235:genetics*; D005260:Female; D006801:Humans; D008133:Long QT Syndrome / Q000235:genetics*; D009154:Mutation; D013575:Syncope / Q000235:genetics*; D016171:Torsades de Pointes / Q000235:genetics*
D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human