Human KCNQ5 de novo mutations underlie epilepsy and intellectual disability

Aguan D. Wei, Paul Wakenight, Theresa A. Zwingman, Angela M. Bard, Nikhil Sahai, Marjolein H. Willemsen, Helenius J. Schelhaas, Alexander P.A. Stegmann, Judith S. Verhoeven, Stella A. De Man, Marja W. Wessels, Tjitske Kleefstra, Deepali N. Shinde, Katherine L. Helbig, Alice Basinger, Victoria F. Wagner, David Rodriguez-Buritic, Emily Bryant, John J. Millichap, Kathleen J. MillenWilliam B. Dobyns, Jan Marino Ramirez, Franck K. Kalume

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


We identified six novel de novo human KCNQ5 variants in children with motor/language delay, intellectual disability (ID), and/or epilepsy by whole exome sequencing. These variants, comprising two nonsense and four missense alterations, were functionally characterized by electrophysiology in HEK293/CHO cells, together with four previously reported KCNQ5 missense variants (Lehman A, Thouta S, Mancini GM, Naidu S, van Slegtenhorst M, McWalter K, Person R, Mwenifumbo J, Salvarinova R; CAUSES Study; EPGEN Study; Guella I, McKenzie MB, Datta A, Connolly MB, Kalkhoran SM, Poburko D, Friedman JM, Farrer MJ, Demos M, Desai S, Claydon T. Am J Hum Genet 101: 65-74, 2017). Surprisingly, all eight missense variants resulted in gain of function (GOF) due to hyperpolarized voltage dependence of activation or slowed deactivation kinetics, whereas the two nonsense variants were confirmed to be loss of function (LOF). One severe GOF allele ( P369T) was tested and found to extend a dominant GOF effect to heteromeric KCNQ5/3 channels. Clinical presentations were associated with altered KCNQ5 channel gating: milder presentations with LOF or smaller GOF shifts in voltage dependence [change in voltage at half-maximal conduction (Δ V 50) = ∼-15 mV] and severe presentations with larger GOF shifts in voltage dependence (Δ V 50 = ∼-30 mV). To examine LOF pathogenicity, two Kcnq5 LOF mouse lines were created with CRISPR/Cas9. Both lines exhibited handling- and thermal-induced seizures and abnormal cortical EEGs consistent with epileptiform activity. Our study thus provides evidence for in vivo KCNQ5 LOF pathogenicity and strengthens the contribution of both LOF and GOF mutations to global pediatric neurological impairment, including ID/epilepsy. NEW & NOTEWORTHY Six novel de novo human KCNQ5 variants were identified from children with neurodevelopmental delay, intellectual disability, and/or epilepsy. Expression of these variants along with four previously reported KCNQ5 variants from a similar cohort revealed GOF potassium channels, negatively shifted in V 50 of activation and/or delayed deactivation kinetics. GOF is extended to KCNQ5/3 heteromeric channels, making these the predominant channels affected in heterozygous de novo patients. Kcnq5 LOF mice exhibited seizures, consistent with in vivo pathogenicity.

Original languageEnglish (US)
Pages (from-to)40-61
Number of pages22
JournalJournal of neurophysiology
Issue number1
StatePublished - 2022

Bibliographical note

Funding Information:
This study was funded by the National Institutes of Health under National Institute of Neurological Disorders and Stroke and National Heart, Lung, and Blood Institute Grants R01NS092772 (W.B.D.), R01HL126523 (J.-M.R.), R01NS102796 (F.K.K.), and R01NS099027 (K. J.M.) and a grant from Citizens United for Research in Epilepsy (CURE) (F.K.K.).

Publisher Copyright:
Copyright © 2022 the American Physiological Society.


  • Channelopathy
  • KCNQ5
  • M current
  • epilepsy
  • intellectual disability
  • Cricetinae
  • Cricetulus
  • Humans
  • Mutation, Missense
  • KCNQ Potassium Channels
  • Intellectual Disability/genetics
  • Animals
  • Epilepsy/genetics
  • HEK293 Cells
  • Mice
  • Child
  • Seizures

PubMed: MeSH publication types

  • Research Support, Non-U.S. Gov't
  • Journal Article
  • Research Support, N.I.H., Extramural


Dive into the research topics of 'Human KCNQ5 de novo mutations underlie epilepsy and intellectual disability'. Together they form a unique fingerprint.

Cite this