Dominant‐negative effects of KCNQ2 mutations are associated with epileptic encephalopathy. Issue 3 (18th March 2014)

• Record Type: Journal Article
• Authors: Orhan, Gökce; Bock, Merle; Schepers, Dorien; Ilina, Elena I.; Reichel, Stephanie Nadine; Löffler, Heidi; Jezutkovic, Nicole; Weckhuysen, Sarah; Mandelstam, Simone; Suls, Arvid; Danker, Timm; Guenther, Elke; Scheffer, Ingrid E.; De, Peter; Lerche, Holger; Maljevic, Snezana
• Is Part Of: Annals of neurology. Volume 75:Issue 3(2014:Mar.)
• Page Start: 382
• Page End: 394
• Publication Date: 2014-03-18
• Subjects: Neurology -- Periodicals; Pediatric neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; 616.8
• DOI: 10.1002/ana.24080
• Languages: English
• ISSNs: 0364-5134

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="ana24080-sec-0001" sec-type="section"> <title>Objective</title> <p>Mutations in <italic>KCNQ2</italic> and <italic>KCNQ3</italic>, encoding the voltage‐gated potassium channels K<sub>V</sub>7.2 and K<sub>V</sub>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 <italic>KCNQ2</italic> mutations that were recently described in patients with a severe epileptic encephalopathy including pharmacoresistant seizures and pronounced intellectual disability.</p> </sec> <sec id="ana24080-sec-0002" sec-type="section"> <title>Methods</title> <p>Mutations were inserted into the <italic>KCNQ2</italic> cDNA. Potassium currents were recorded using 2‐microelectrode voltage clamping, and surface expression was analyzed by a biotinylation assay in cRNA‐injected <italic>Xenopus laevis</italic> oocytes.</p> </sec> <sec id="ana24080-sec-0003" sec-type="section"> <title>Results</title> <p>We observed a clear loss of function for all mutations. Strikingly, 5 of 7 mutations exhibited a drastic dominant‐negative effect on wild‐type K<sub>V</sub>7.2 or K<sub>V</sub>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 K<sub>V</sub>7 channel opener, partially reversed these effects for the majority of analyzed mutations.</p> </sec> <sec id="ana24080-sec-0004" sec-type="section"> <title>Interpretation</title> <p>The development of severe epilepsy and cognitive decline in children carrying 5 of the 7 studied <italic>KCNQ2</italic> 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. Ann Neurol 2014;75:382–394</p> </sec> </abstract>