Dominant-negative effects of KCNQ2 mutations are associated with epileptic encephalopathy

Gökce Orhan, Merle Bock, Dorien Schepers, Elena I Ilina, Stephanie Nadine Reichel, Heidi Löffler, Nicole Jezutkovic, Sarah Weckhuysen, Simone Mandelstam, Arvid Suls, Timm Danker, Elke Guenther, Ingrid E Scheffer, Peter De Jonghe, Holger Lerche, Snezana Maljevic
Annals of Neurology 2014, 75 (3): 382-94

OBJECTIVE: Mutations in KCNQ2 and KCNQ3, encoding the voltage-gated potassium channels KV 7.2 and KV 7.3, are known to cause benign familial neonatal seizures mainly by haploinsufficiency. Here, we set out to determine the disease mechanism of 7 de novo missense KCNQ2 mutations that were recently described in patients with a severe epileptic encephalopathy including pharmacoresistant seizures and pronounced intellectual disability.

METHODS: Mutations were inserted into the KCNQ2 cDNA. Potassium currents were recorded using 2-microelectrode voltage clamping, and surface expression was analyzed by a biotinylation assay in cRNA-injected Xenopus laevis oocytes.

RESULTS: We observed a clear loss of function for all mutations. Strikingly, 5 of 7 mutations exhibited a drastic dominant-negative effect on wild-type KV 7.2 or KV 7.3 subunits, either by globally reducing current amplitudes (3 pore mutations) or by a depolarizing shift of the activation curve (2 voltage sensor mutations) decreasing potassium currents at the subthreshold level at which these channels are known to critically influence neuronal firing. One mutation significantly reduced surface expression. Application of retigabine, a recently marketed KV 7 channel opener, partially reversed these effects for the majority of analyzed mutations.

INTERPRETATION: The development of severe epilepsy and cognitive decline in children carrying 5 of the 7 studied KCNQ2 mutations can be related to a dominant-negative reduction of the resulting potassium current at subthreshold membrane potentials. Other factors such as genetic modifiers have to be postulated for the remaining 2 mutations. Retigabine or similar drugs may be used as a personalized therapy for this severe disease.

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