title: Dominant-negative effects of KCNQ2 mutations are associated with epileptic encephalopathy.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors: Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany.
authors: Gökce
authors: G
authors: Orhan
authors: Merle
authors: M
authors: Bock
authors: Dorien
authors: D
authors: Schepers
authors: Elena I
authors: EI
authors: Ilina
authors: Stephanie Nadine
authors: SN
authors: Reichel
authors: Heidi
authors: H
authors: Löffler
authors: Nicole
authors: N
authors: Jezutkovic
authors: Sarah
authors: S
authors: Weckhuysen
authors: Simone
authors: S
authors: Mandelstam
authors: Arvid
authors: A
authors: Suls
authors: Timm
authors: T
authors: Danker
authors: Elke
authors: E
authors: Guenther
authors: Ingrid E
authors: IE
authors: Scheffer
authors: Peter
authors: P
authors: De Jonghe
authors: Holger
authors: H
authors: Lerche
authors: Snezana
authors: S
authors: Maljevic
mesh_terms: D000818:Animals; D002219:Carbamates / Q000494:pharmacology; D020936:Epilepsy, Benign Neonatal / Q000235:genetics* / Q000503:physiopathology; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D051658:KCNQ2 Potassium Channel / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D008564:Membrane Potentials / Q000235:genetics; D020125:Mutation, Missense; D009865:Oocytes; D010655:Phenylenediamines / Q000494:pharmacology; D024642:Potassium Channels, Voltage-Gated / Q000187:drug effects / Q000235:genetics* / Q000502:physiology; D014981:Xenopus
chemical_list: D002219:Carbamates; D051658:KCNQ2 Potassium Channel; D010655:Phenylenediamines; D024642:Potassium Channels, Voltage-Gated; C101866:ezogabine