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NEUROLOGY 2008;71:177-183
© 2008 American Academy of Neurology

KCNQ2 and KCNQ3 mutations contribute to different idiopathic epilepsy syndromes

B. A. Neubauer, MD, S. Waldegger, MD, J. Heinzinger, MD, A. Hahn, MD, G. Kurlemann, MD, B. Fiedler, MD, F. Eberhard, MD, H. Muhle, MD, U. Stephani, MD, S. Garkisch, O. Eeg-Olofsson, MD, U. Müller, MD and T. Sander, MD

From the Departments of Pediatric Neurology (B.A.N., A.H., F.E., S.G.) and Human Genetics (U.M.), University of Giessen-Marburg, Giessen, Germany; Department of Pediatrics (S.W., J.H.), University of Giessen-Marburg, Marburg, Germany; Department of Pediatric Neurology (G.K., B.F.), University of Muenster, Germany; Department of Pediatric Neurology (H.M., U.S.), University of Kiel, Germany; Department of Women’s and Children’s Health (O.E.-O.), Uppsala University, Sweden; and Cologne Center for Genomics (T.S.), University of Cologne, Germany.

Address correspondence and reprint requests to Dr. Bernd A. Neubauer, Department of Pediatric Neurology, University of Giessen-Marburg, Feulgenstrasse 12, D-35385 Giessen, Germany

Objective: To explore the involvement of M-type potassium channels KCNQ2, Q3, and Q5 in the pathogenesis of common idiopathic epilepsies.

Methods: Sequence analysis of the KCNQ2, Q3, and Q5 coding regions was performed in a screening sample consisting of 58 nuclear families with rolandic epilepsy. Subsequently, an association study was conducted for all discovered variants in a case–control sample comprising 459 German patients with idiopathic generalized epilepsy (IGE) and 462 population controls.

Results: An in-frame deletion of codon 116 in KCNQ2 (p.Lys116del) and a missense mutation in KCNQ3 (p.Glu299Lys) were detected in two index cases exhibiting rolandic epilepsy and benign neonatal convulsions. Both mutations resulted in reduced potassium current amplitude in Xenopus oocytes. Mutation analysis of families with rolandic epilepsy without neonatal seizures discovered three novel missense variations (KCNQ2 p.Ile592Met, KCNQ3 p.Ala381Val, KCNQ3 p.Pro574Ser). The KCNQ2 p.Ile592Met variant displayed a significant reduction of potassium current amplitude in Xenopus oocytes and was present only once in 552 controls. Both missense variants identified in KCNQ3 (p.Ala381Val and p.Pro574Ser) were present in all affected family members and did not occur in controls, but did not show obvious functional abnormalities. The KCNQ3 missense variant p.Pro574Ser was also detected in 8 of 455 IGE patients but not in 454 controls (p = 0.008). In KCNQ2, a silent single nucleotide polymorphism (rs1801545) was found overrepresented in both epilepsy samples (IGE, p = 0.004).

Conclusion: Sequence variations of the KCNQ2 and KCNQ3 genes may contribute to the etiology of common idiopathic epilepsy syndromes.

GLOSSARY: BNFC = benign neonatal familial convulsions; bp = base pair; cRNA = complementary RNA; IAE = idiopathic absence epilepsy; IE = idiopathic epilepsy; IGE = idiopathic generalized epilepsy; JME = juvenile myoclonic epilepsy; OR = odds ratio; RE = rolandic epilepsy; SNP = single nucleotide polymorphism; WT = wild type.

bernd.a.neubauer{at}paediat.med.uni-giessen.de

Supported by grants of the Deutsche Forschungsgemeinschaft (SA434/4-1 to T.S.), the German Federal Ministry of Education and Research (BMBF/NGFN2: 01GS0479 to T.S.), and the European Integrated Project EPICURE (EC contract number: LSH-CT-2006-037315 to T.S.).

Disclosure: The authors report no disclosures.

Supplemental data at www.neurology.org

Received September 10, 2007. Accepted in final form April 1, 2008.




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