Homomeric Kv7.2 current suppression is a common feature in <i><scp>KCNQ</scp>2</i> epileptic encephalopathy

Gomis-Pérez, Carolina; Urrutia, Janire; Marcé‐Grau, Anna; Malo, Covadonga; López‐Laso, Eduardo; Felipe‐Rucián, Ana; Raspall-Chaure, Miquel; Macaya, Alfons; Villarroel, Álvaro

doi:10.1111/epi.14609

Cited by 25 publications

(33 citation statements)

References 32 publications

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“…All other single-substituted Kv7.2 channels herein investigated were functional, and showed a rightward shift in their activation gating (Figure 5; Table 1), confirming that each residue plays a prevalent role in the stabilization of the Kv7.2 activated state. Consistent with our results is the LoF effect observed in Kv7.1 [45,46] or Kv7.2 [38,42] when the charges at E1, R4, R5, and R6 are neutralized or reversed.…”

Section: Resultssupporting

confidence: 92%

“…The Kv7.2 E2Q mutation has been identified de novo on a single Kv7.2 allele; thus, homomeric channels composed of only mutant subunits represent a very small proportion of channels formed in vivo. Furthermore, while most I KM in adult superior cervical ganglion neurons are Kv7.2/Kv7.3 heterotetramers [34], expression of Kv7.2 precedes that of Kv7.3 in both rodent and human brains [35,36,37], and the severity of the Kv7.2 encephalopathy has been correlated to a mutation-induced dysfunction of homomeric Kv7.2 channels, possibly because of their critical role in fine-tuning neuronal connections during development [38]. Therefore, Kv7.2 E140Q subunits were co-expressed both with wild-type Kv7.2 subunits and wild-type Kv7.2 and Kv7.3 subunits.…”

Section: Resultsmentioning

confidence: 99%

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Epileptic Encephalopathy In A Patient With A Novel Variant In The Kv7.2 S2 Transmembrane Segment: Clinical, Genetic, and Functional Features

Soldovieri

Ambrosino

Mosca

et al. 2019

IJMS

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Kv7.2 subunits encoded by the KCNQ2 gene provide a major contribution to the M-current (IKM), a voltage-gated K+ current crucially involved in the regulation of neuronal excitability. Heterozygous missense variants in Kv7.2 are responsible for epileptic diseases characterized by highly heterogeneous genetic transmission and clinical severity, ranging from autosomal-dominant Benign Familial Neonatal Seizures (BFNS) to sporadic cases of severe epileptic and developmental encephalopathy (DEE). Here, we describe a patient with neonatal onset DEE, carrying a previously undescribed heterozygous KCNQ2 c.418G > C, p.Glu140Gln (E140Q) variant. Patch-clamp recordings in CHO cells expressing the E140Q mutation reveal dramatic loss of function (LoF) effects. Multistate structural modelling suggested that the E140Q substitution impeded an intrasubunit electrostatic interaction occurring between the E140 side chain in S2 and the arginine at position 210 in S4 (R210); this interaction is critically involved in stabilizing the activated configuration of the voltage-sensing domain (VSD) of Kv7.2. Functional results from coupled charge reversal or disulfide trapping experiments supported such a hypothesis. Finally, retigabine restored mutation-induced functional changes, reinforcing the rationale for the clinical use of Kv7 activators as personalized therapy for DEE-affected patients carrying Kv7.2 LoF mutations.

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Section: Resultssupporting

confidence: 92%

Section: Resultsmentioning

confidence: 99%

Epileptic Encephalopathy In A Patient With A Novel Variant In The Kv7.2 S2 Transmembrane Segment: Clinical, Genetic, and Functional Features

Soldovieri

Ambrosino

Mosca

et al. 2019

IJMS

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“…6), which is shown to play critical roles in M-current expression and inhibition of hippocampal neuronal excitability 53 . Current suppression of homomeric channels is a common feature of EE variants of KCNQ2 54 . Given the overlapping distribution of K v 7.2 and K v 7.3 throughout the hippocampus and cortex 4 , the dominant negative functional effects of L268F and K552T variants on heteromeric channels (Figs.…”

Section: Discussionmentioning

confidence: 99%

Identifying mutation hotspots reveals pathogenetic mechanisms of KCNQ2 epileptic encephalopathy

Zhang

Kim

Chen

et al. 2020

Sci Rep

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K v 7 channels are enriched at the axonal plasma membrane where their voltage-dependent potassium currents suppress neuronal excitability. Mutations in K v 7.2 and K v 7.3 subunits cause epileptic encephalopathy (EE), yet the underlying pathogenetic mechanism is unclear. Here, we used novel statistical algorithms and structural modeling to identify EE mutation hotspots in key functional domains of K v 7.2 including voltage sensing S4, the pore loop and S6 in the pore domain, and intracellular calmodulin-binding helix B and helix B-C linker. Characterization of selected EE mutations from these hotspots revealed that L203P at S4 induces a large depolarizing shift in voltage dependence of K v 7.2 channels and L268F at the pore decreases their current densities. While L268F severely reduces expression of heteromeric channels in hippocampal neurons without affecting internalization, K552T and R553L mutations at distal helix B decrease calmodulin-binding and axonal enrichment. Importantly, L268F, K552T, and R553L mutations disrupt current potentiation by increasing phosphatidylinositol 4,5-bisphosphate (PIP 2), and our molecular dynamics simulation suggests PIP 2 interaction with these residues. Together, these findings demonstrate that each EE variant causes a unique combination of defects in K v 7 channel function and neuronal expression, and suggest a critical need for both prediction algorithms and experimental interrogations to understand pathophysiology of K v 7-associated EE. Epilepsy is the second most prominent neurological disease (www.epilepsy.com), in which excessive electrical activity within networks of neurons in the brain manifests clinically as recurrent unprovoked seizures 1. Recent discoveries of epilepsy-related genes in multiple laboratories and through large consortia have revealed a diverse array of proteins that may contribute to epileptogenesis 1,2. Among these proteins, neuronal KCNQ/K v 7 potassium (K +) channels have been implicated in epilepsy since mutations in the principle subunits, KCNQ2/K v 7.2 and KCNQ3/K v 7.3, cause Benign Familial Neonatal Epilepsy (BFNE [MIM: 121200]) and Epileptic Encephalopathy (EE [MIM: 613720]) (RIKEE database www.rikee.org). Neuronal K v 7 channels are mainly composed of heterotetramers of K v 7.2 and K v 7.3 3 , which show overlapping distribution in the hippocampus and cortex 4. They generate slowly activating and non-inactivating voltage-dependent K + currents that contribute to resting membrane potential, prevent repetitive and burst firing of action potentials (APs), and modulate AP threshold 3,5-7 .They are enriched at the plasma membrane of axonal initial segments (AIS) and distal axons 8,9 , where APs initiate and propagate 10. Membrane phosphatidylinositol-4,5-bisphosphate (PIP 2) is required for K v 7 channels to open 3 , although its exact binding sites in K v 7.2 and K v 7.3

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“…The prediction of the molecular model is compatible with the results of research on electrophysiological properties. Several studies have claimed that homomeric current change is common in KCNQ2 neonatal-onset EE 28,29,36,40 . In contrast, we found that heteromeric functional current changes are correlated with long-term neurodevelopmental outcomes.…”

Section: Discussionmentioning

confidence: 99%

“…However, the factors contributing to long-term neurodevelopmental outcomes are multiple and complex, including genotype, genetic mosaicism, modified genes, duration of seizures, and environmental factors 6 – 8 , 37 . Homomeric current changes in KCNQ2 mutations were common in KCNQ2 mutations, suggesting loss of the ability to regulate neuronal firing 40 . However, in this study, the homomeric current changes were not necessarily associated with later neurodevelopmental outcomes.…”

Section: Discussionmentioning

confidence: 99%

Heteromeric Kv7.2 current changes caused by loss-of-function of KCNQ2 mutations are correlated with long-term neurodevelopmental outcomes

Lee

Yang

Wong

et al. 2020

Sci Rep

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Pediatric epilepsy caused by KCNQ2 mutations can manifest benign familial neonatal convulsions (BFNC) to neonatal-onset epileptic encephalopathy (EE). Patients might manifest mild to profound neurodevelopmental disabilities. We analysed c.853C > A (P285T) and three mutations that cause KCNQ2 protein changes in the 247 position: c.740C > T (S247L), c.740C > A (S247X), and c.740C > G (S247W). S247L, S247W, and P285T cause neonatal-onset EE and poor neurodevelopmental outcomes; S247X cause BFNC and normal outcome. We investigated the phenotypes correlated with human embryonic kidney 293 (HEK293) cell functional current changes. More cell-current changes and a worse conductance curve were present in the homomeric transfected S247X than in S247L, S247W, and P285T. But in the heteromeric channel, S247L, S247W and P285T had more current impairments than did S247X. The protein expressions of S247X were nonfunctional. The outcomes were most severe in S247L and S247W, and severity was correlated with heteromeric current. Current changes were more significant in cells with homomeric S247X, but currents were "rescued" after heteromeric transfection of KCNQ2 and KCNQ3. This was not the case in cells with S247L, S247W. Our findings support that homomeric current changes are common in KCNQ2 neonatal-onset EE and KCNQ2 BFNC; however, heteromeric functional current changes are correlated with long-term neurodevelopmental outcomes. KCNQ2 (OMIM 602235)-associated seizures usually occur during the first week after birth and can contribute to benign familial neonatal convulsions (BFNC), benign familial neonatal-infantile seizures (BFNIS), benign familial infantile seizures (BFIS) 1-5 , and neonatal-onset epileptic encephalopathy (EE) 6-8. Mutations in KCNQ2, a voltage-gated potassium channel gene at 20q13, are usually inherited in an autosomal-dominant manner in benign epileptic syndromes 1,2. Patients with BFNC usually have seizures with a predicted benign course and predicted good neurodevelopmental outcomes 1-3,9,10. On follow-up, about 30% of patients with inherited KCNQ2 mutations might have recurrent seizures beyond neonatal age 10. Most neonatal-onset EE, mutations are de novo, and patients present with severe seizures and grave neurological consequences. Seizures often remit as the patients become older, but the patients usually have intellectual developmental delays or autism 11,12. At present, however, outcomes cannot be accurately predicted. Functional KCNQ channels are homo-or heteromers of four subunits each containing 6 transmembrane domains (S1-S6), which include a voltage sensor in S1-S4 and S5-S6, and a loop between S5-S6 that builds the ion channel pore, a cytoplasmic N-terminal, and a long C-terminal region with complex functions exhibiting interactions between syntaxin, phosphatidylinositol 4,5-bisphosphate, ankyrin-G, Syn-1A, and A-kinase

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Homomeric Kv7.2 current suppression is a common feature in KCNQ2 epileptic encephalopathy

Cited by 25 publications

References 32 publications

Epileptic Encephalopathy In A Patient With A Novel Variant In The Kv7.2 S2 Transmembrane Segment: Clinical, Genetic, and Functional Features

Epileptic Encephalopathy In A Patient With A Novel Variant In The Kv7.2 S2 Transmembrane Segment: Clinical, Genetic, and Functional Features

Identifying mutation hotspots reveals pathogenetic mechanisms of KCNQ2 epileptic encephalopathy

Heteromeric Kv7.2 current changes caused by loss-of-function of KCNQ2 mutations are correlated with long-term neurodevelopmental outcomes

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