Gain of function due to increased opening probability by two
            <i>KCNQ5</i>
            pore variants causing developmental and epileptic encephalopathy

Nappi, Mario; Barrese, Vincenzo; Carotenuto, Lidia; Lesca, Gaëtan; Labalme, Audrey; Ville, Dorothée; Smol, Thomas; Rama, Mélanie; Dieux-Coëslier, Anne; Rivier-Ringenbach, Clotilde; Soldovieri, Maria Virginia; Ambrosino, Paolo; Mosca, Ilaria; Pusch, Michael; Miceli, Francesco; Taglialatela, Maurizio

doi:10.1073/pnas.2116887119

Cited by 24 publications

(19 citation statements)

References 52 publications

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“… 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). While global developmental delay of varying degree is a common feature in all descripted individuals in the above mentioned studies, three of our variants were not associated with ID (L692V, Q735R and A301Gfs*64) and the family carrying the R359C variant shows a spectrum with one individual being unaffected to individuals with mild to moderate ID.…”

Section: Discussionmentioning

confidence: 52%

“…We could not find clear genotype-phenotype correlations within our study, since (i) family 1 carrying the most severe variant displays a large phenotypic heterogeneity ranging from mildly to severely affected, pharmaco-resistant individuals, (ii) individuals in family 3 exhibited a similarly severe epileptic phenotype albeit the Q735R variant showed a less prominent electrophysiological dysfunction, and (iii) also the phenotype of previously reported individuals carrying variants which only caused haploinsufficiency were reported with similar or more severe phenotypes. 16 , 17 , 18 , 19 This is in contrast to other K v 7 channels, in which functionally more severe variants with dominant-negative effects cause more severe epileptic phenotypes. 35 Looking at our results in the context of the newly published variants, it seems that individuals carrying LOF variants display milder phenotypes, while GOF variants cause more severe phenotypes, such as DEE.…”

Section: Discussionmentioning

confidence: 93%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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Section: Discussionmentioning

confidence: 52%

Section: Discussionmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

et al. 2022

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“…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 ].…”

Section: Discussionmentioning

confidence: 99%

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

Bauer

Holling

Horn

et al. 2022

IJMS

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Dominant KCNQ1 variants are well-known for underlying cardiac arrhythmia syndromes. The two heterozygous KCNQ1 missense variants, R116L and P369L, cause an allelic disorder characterized by pituitary hormone deficiency and maternally inherited gingival fibromatosis. Increased K+ conductance upon co-expression of KCNQ1 mutant channels with the beta subunit KCNE2 is suggested to underlie the phenotype; however, the reason for KCNQ1-KCNE2 (Q1E2) channel gain-of-function is unknown. We aimed to discover the genetic defect in a single individual and three family members with gingival overgrowth and identified the KCNQ1 variants P369L and V185M, respectively. Patch-clamp experiments demonstrated increased constitutive K+ conductance of V185M-Q1E2 channels, confirming the pathogenicity of the novel variant. To gain insight into the pathomechanism, we examined all three disease-causing KCNQ1 mutants. Manipulation of the intracellular Ca2+ concentration prior to and during whole-cell recordings identified an impaired Ca2+ sensitivity of the mutant KCNQ1 channels. With low Ca2+, wild-type KCNQ1 currents were efficiently reduced and exhibited a pre-pulse-dependent cross-over of current traces and a high-voltage-activated component. These features were absent in mutant KCNQ1 channels and in wild-type channels co-expressed with calmodulin and exposed to high intracellular Ca2+. Moreover, co-expression of calmodulin with wild-type Q1E2 channels and loading the cells with high Ca2+ drastically increased Q1E2 current amplitudes, suggesting that KCNE2 normally limits the resting Q1E2 conductance by an increased demand for calcified calmodulin to achieve effective channel opening. Our data link impaired Ca2+ sensitivity of the KCNQ1 mutants R116L, V185M and P369L to Q1E2 gain-of-function that is associated with a particular KCNQ1 channelopathy.

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“…This is in contrast to the early onset phenotypes observed in patients with LOF variants in KCNQ2 and KCNQ3 that cause self-limited familial neonatal epilepsy (SLFNE) or developmental and epileptic encephalopathy (DEE; Singh et al 1998, Charlier et al 1998, Weckhuysen et al 2012). Pathogenic gain-of-function (GOF) variants were described in severe intellectual disability (ID) with or without seizures, and DEE (Lehman et al 2017, Nappi et al 2022, Wei et al 2022). Additionally, two truncating variants in less severely affected individuals and an intragenic duplication in a patient with absence seizures, migraine, and mild ID have been reported, all resulting in a haploinsufficiency (Wei et al 2022, Rosti et al 2019).…”

Section: Introductionmentioning

confidence: 99%

Retigabine and gabapentin restore channel function and neuronal firing of an epilepsy-associated dominant-negativeKCNQ5variant

Krüger

Lerche

2023

Preprint

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Objective:KCNQ5encodes the voltage-gated potassium channel KV7.5, a member of the KV7 channel family, which conducts the M-current. This current was shown to be a potent regulator of neuronal excitability by mediating the medium and slow afterhyperpolarization. Recently, we have identified five loss-of-function variants inKCNQ5in patients with genetic generalized epilepsy. Using the most severe dominant-negative variant p.(Arg359Cys) (R359C), we set out to investigate pharmacological therapeutic intervention by KV7 channel openers on channel function and neuronal firing. Methods: Whole-cell patch clamp recordings were conducted in human embryonic kidney cells to investigate the immediate effect of retigabine, gabapentin and intracellular application of zinc on the R359C variant in absence and presence of KV7.5-WT subunits. Transfected primary hippocampal cultures were used to examine the effect of R359C on neuronal firing and whether this effect could be reversed by drug application. Results: Retigabine and gabapentin both increased R359C-derived K+current density and M-current amplitudes in both homomeric and heteromeric mutant KV7.5 channels. Retigabine was most effective in restoring K+currents. Ten μM retigabine was sufficient to reach the level of WT currents without retigabine, whereas 100 μM of gabapentin showed less than half of this effect and application of 50 μM zinc only significantly increased M-current amplitude in heteromeric channels. Overexpression of KV7.5-WT potently inhibited neuronal firing by increasing the M-current, and medium afterhyperpolarization, whereas R359C overexpression had the opposite effect. All three aforementioned drugs reversed the effect of R359C reducing firing to nearly normal levels at high current injections. Significance: Our study shows that a dominant-negative complete loss-of-function variant in KV7.5 leads to largely increased neuronal firing indicating a neuronal hyperexcitability. KV7 channel openers, such as retigabine or gabapentin, could be treatment options for otherwise pharmacoresistant epilepsy patients carrying loss-of-function variants inKCNQ5.

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Gain of function due to increased opening probability by two KCNQ5 pore variants causing developmental and epileptic encephalopathy

Cited by 24 publications

References 52 publications

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

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

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

Retigabine and gabapentin restore channel function and neuronal firing of an epilepsy-associated dominant-negativeKCNQ5variant

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