Human KCNQ5 de novo mutations underlie epilepsy and intellectual disability

Abstract

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 comprised of two nonsense and four missense alterations, were functionally characterized by electrophysiology in HEK293/CHO cells, together with four previously reported KCNQ5 missense variants (Lehman, et al., 2017). Surprisingly, all eight missense variants resulted in gain-of-function (GOF) due to hyperpolarized voltage-dependence of activation or slowed deactivation kinetics, while 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 (DV50= ~-15 mV), and severe presentations with larger GOF shifts in voltage-dependence (DV50= ~-30 mV). To examine LOF pathogenicity, two Kcnq5 LOF mouse lines were created using 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.

Loss-of-function variants in the KCNQ5 gene are implicated in genetic generalized epilepsies

“…Moreover, this study shows that the more severe GOF variants were found in more severely affected individuals, while milder GOF variants and the truncating LOF variants belonged to individuals with a milder phenotype. 17 This is in line with a second recent publication that found two pore variants to cause a GOF in individuals with DEE. 18 The individuals presented here show a milder phenotype as compared to the three studies mentioned and two carriers were even asymptomatic (one with R359C and one with Q735R).…”

“…Additionally, the functional severity of the GOF seems to correlate with the severity in the phenotype of the patient. 17 Similar patterns of GOF variants inducing much more severe phenotypes such as DEE and LOF variants inducing milder phenotypes such as GGE have been described for other genes such as SCN8A, 36 SCN2A 37 and KCNA2. 38 For KCNQ5 , it seems that any significant LOF can contribute to an epileptic phenotype or ID of varying severity, which might be influenced by other individually differing factors, such as compensatory effects, the genetic background or environmental determinants.…”

“…13,14,15 More recently, de novo heterozygous missense and truncating variants in KCNQ5 in individuals with intellectual disability (ID) alone or with DEE have been described. 16,17,18 Additionally, an individual presenting with absence seizures in adolescence, migraine and mild ID has recently been identified with an intragenic duplication of KCNQ5 most likely causing haploinsufficiency by skipping exons 2-11 and resulting in a premature stop codon. 19 Here, we analysed different cohorts of GGE patients to identify causative variants in KCNQ5, studied the phenotypes of affected individuals and co-segregation of the detected variants.…”

Clinically Relevant KCNQ1 Variants Causing KCNQ1-KCNE2 Gain-of-Function Affect the Ca2+ Sensitivity of the Channel

“…Hence, the pronounced insensitivity to Ca 2+ of P369L homomeric KCNQ1 and heteromeric Q1E2 channels could rely on a downstream mechanism circumventing the primary Ca 2+ -sensing process. The functional importance of a proline at this position for all KCNQ family members is indicated by the gain-of-function of the KCNQ5 variants P369R and P369T, affecting the proline analogous to KCNQ1 P369 [ 53 , 54 ]. Heterozygous gain- and loss-of-function variants in KCNQ5 cause pediatric neurological disorders of different severities [ 53 , 54 , 55 ].…”

“…The functional importance of a proline at this position for all KCNQ family members is indicated by the gain-of-function of the KCNQ5 variants P369R and P369T, affecting the proline analogous to KCNQ1 P369 [ 53 , 54 ]. Heterozygous gain- and loss-of-function variants in KCNQ5 cause pediatric neurological disorders of different severities [ 53 , 54 , 55 ].…”