TY - JOUR
T1 - Human KCNQ5 de novo mutations underlie epilepsy and intellectual disability
AU - Wei, Aguan D.
AU - Wakenight, Paul
AU - Zwingman, Theresa A.
AU - Bard, Angela M.
AU - Sahai, Nikhil
AU - Willemsen, Marjolein H.
AU - Schelhaas, Helenius J.
AU - Stegmann, Alexander P.A.
AU - Verhoeven, Judith S.
AU - De Man, Stella A.
AU - Wessels, Marja W.
AU - Kleefstra, Tjitske
AU - Shinde, Deepali N.
AU - Helbig, Katherine L.
AU - Basinger, Alice
AU - Wagner, Victoria F.
AU - Rodriguez-Buritic, David
AU - Bryant, Emily
AU - Millichap, John J.
AU - Millen, Kathleen J.
AU - Dobyns, William B.
AU - Ramirez, Jan Marino
AU - Kalume, Franck K.
N1 - Publisher Copyright:
Copyright © 2022 the American Physiological Society.
PY - 2022
Y1 - 2022
N2 - 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 (ΔV50) = ~-15 mV] and severe presentations with larger GOF shifts in voltage dependence (ΔV50 = ~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.
AB - 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 (ΔV50) = ~-15 mV] and severe presentations with larger GOF shifts in voltage dependence (ΔV50 = ~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.
KW - Channelopathy
KW - KCNQ5
KW - M current
KW - epilepsy
KW - intellectual disability
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UR - http://www.scopus.com/inward/citedby.url?scp=85133102657&partnerID=8YFLogxK
U2 - 10.1152/jn.00509.2021
DO - 10.1152/jn.00509.2021
M3 - Article
C2 - 35583973
AN - SCOPUS:85133102657
SN - 0022-3077
VL - 128
SP - 40
EP - 61
JO - Journal of neurophysiology
JF - Journal of neurophysiology
IS - 1
ER -