Human KCNQ5 de novo mutations underlie epilepsy and intellectual disability (original) (raw)
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Loss-of-function variants in the KCNQ5 gene are associated with genetic generalized epilepsies
2021
ABSTRACTObjectiveDe novo missense variants in KCNQ5, encoding the voltage-gated K+ channel KV7.5, have been described as a cause of developmental and epileptic encephalopathy (DEE) or intellectual disability (ID). We set out to identify disease-related KCNQ5 variants in genetic generalized epilepsy (GGE) and their underlying mechanisms.Methods1292 families with GGE were studied by next-generation sequencing. Whole-cell patch-clamp recordings, biotinylation and phospholipid overlay assays were performed in mammalian cells combined with docking and homology modeling.ResultsWe identified three deleterious heterozygous missense variants, one truncation and one splice site alteration in five independent families with GGE with predominant absence seizures, two variants were also associated with mild to moderate ID. All three missense variants displayed a strongly decreased current density indicating a loss-of-function (LOF). When mutant channels were co-expressed with wild-type (WT) KV7.5...
American journal of human genetics, 2017
KCNQ5 is a highly conserved gene encoding an important channel for neuronal function; it is widely expressed in the brain and generates M-type current. Exome sequencing identified de novo heterozygous missense mutations in four probands with intellectual disability, abnormal neurological findings, and treatment-resistant epilepsy (in two of four). Comprehensive analysis of this potassium channel for the four variants expressed in frog oocytes revealed shifts in the voltage dependence of activation, including altered activation and deactivation kinetics. Specifically, both loss-of-function and gain-of-function KCNQ5 mutations, associated with increased excitability and decreased repolarization reserve, lead to pathophysiology.
Dominant-negative effects of KCNQ2 mutations are associated with epileptic encephalopathy
Annals of Neurology, 2014
Objective: Mutations in KCNQ2 and KCNQ3, encoding the voltage-gated potassium channels K V 7.2 and K V 7.3, are known to cause benign familial neonatal seizures mainly by haploinsufficiency. Here, we set out to determine the disease mechanism of 7 de novo missense KCNQ2 mutations that were recently described in patients with a severe epileptic encephalopathy including pharmacoresistant seizures and pronounced intellectual disability. Methods: Mutations were inserted into the KCNQ2 cDNA. Potassium currents were recorded using 2microelectrode voltage clamping, and surface expression was analyzed by a biotinylation assay in cRNA-injected Xenopus laevis oocytes. Results: We observed a clear loss of function for all mutations. Strikingly, 5 of 7 mutations exhibited a drastic dominant-negative effect on wild-type K V 7.2 or K V 7.3 subunits, either by globally reducing current amplitudes (3 pore mutations) or by a depolarizing shift of the activation curve (2 voltage sensor mutations) decreasing potassium currents at the subthreshold level at which these channels are known to critically influence neuronal firing. One mutation significantly reduced surface expression. Application of retigabine, a recently marketed K V 7 channel opener, partially reversed these effects for the majority of analyzed mutations. Interpretation: The development of severe epilepsy and cognitive decline in children carrying 5 of the 7 studied KCNQ2 mutations can be related to a dominant-negative reduction of the resulting potassium current at subthreshold membrane potentials. Other factors such as genetic modifiers have to be postulated for the remaining 2 mutations. Retigabine or similar drugs may be used as a personalized therapy for this severe disease. ANN NEUROL 2014;75:382-394 T he neuronal voltage-gated potassium channels K V 7.2 and K V 7.3, encoded by KCNQ2 and KCNQ3 genes, are mutated in benign familial neonatal seizures (BFNS), an autosomal dominant epilepsy syndrome characterized by brief seizures beginning in the first days of life and resolving spontaneously after weeks to months.
A novel KCNQ3 mutation in familial epilepsy with focal seizures and intellectual disability
Epilepsia, 2014
Mutations in the KCNQ2 gene encoding for voltage-gated potassium channel subunits have been found in patients affected with early onset epilepsies with wide phenotypic heterogeneity, ranging from benign familial neonatal seizures (BFNS) to epileptic encephalopathy with cognitive impairment, drug resistance, and characteristic electroencephalography (EEG) and neuroradiologic features. By contrast, only few KCNQ3 mutations have been rarely described, mostly in patients with typical BFNS. We report clinical, genetic, and functional data from a family in which early onset epilepsy and neurocognitive deficits segregated with a novel mutation in KCNQ3 (c.989G>T; p.R330L). Electrophysiological studies in mammalian cells revealed that incorporation of KCNQ3 R330L mutant subunits impaired channel function, suggesting a pathogenetic role for such mutation. The degree of functional impairment of channels incorporating KCNQ3 R330L subunits was larger than that of channels carrying another KCNQ3 mutation affecting the same codon but leading to a different amino acid substitution (p.R330C), previously identified in two families with typical BFNS. These data suggest that mutations in KCNQ3, similarly to KCNQ2, can be found in patients with more severe phenotypes including intellectual disability, and that the degree of the functional impairment caused by mutations at position 330 in KCNQ3 may contribute to clinical disease severity.
Journal of Neuroscience, 2007
Heteromeric assembly of KCNQ2 and KCNQ3 subunits underlie the M-current (I KM ), a slowly activating and noninactivating neuronal K ϩ current. Mutations in KCNQ2 and KCNQ3 genes cause benign familial neonatal convulsions (BFNCs), a rare autosomal-dominant epilepsy of the newborn. In the present study, we describe the identification of a novel KCNQ2 heterozygous mutation (c587t) in a BFNC-affected family, leading to an alanine to valine substitution at amino acid position 196 located at the N-terminal end of the voltage-sensing S 4 domain. The consequences on KCNQ2 subunit function prompted by the A196V substitution, as well as by the A196V/L197P mutation previously described in another BFNC-affected family, were investigated by macroscopic and single-channel current measurements in CHO cells transiently transfected with wild-type and mutant subunits. When compared with KCNQ2 channels, homomeric KCNQ2 A196V or A196V/L197P channels showed a 20 mV rightward shift in their activation voltage dependence, with no concomitant change in maximal open probability or single-channel conductance. Furthermore, current activation kinetics of KCNQ2 A196V channels displayed an unusual dependence on the conditioning prepulse voltage, being markedly slower when preceded by prepulses to more depolarized potentials. Heteromeric channels formed by KCNQ2 A196V and KCNQ3 subunits displayed gating changes similar to those of KCNQ2 A196V homomeric channels. Collectively, these results reveal a novel role for noncharged residues in the N-terminal end of S 4 in controlling gating of I KM and suggest that gating changes caused by mutations at these residues may decrease I KM function, thus causing neuronal hyperexcitability, ultimately leading to neonatal convulsions.
Scientific Reports, 2020
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
Neuronal KCNQ potassium channels:physislogy and role in disease
2000
Humans have over 70 potassium channel genes, but only some of these have been linked to disease. In this respect, the KCNQ family of potassium channels is exceptional: mutations in four out of five KCNQ genes underlie diseases including cardiac arrhythmias, deafness and epilepsy. These disorders illustrate the different physiological functions of KCNQ channels, and provide a model for the
Nine patients with KCNQ2-related neonatal seizures and functional studies of two missense variants
Scientific Reports
Mutations in KCNQ2 encoding for voltage-gated K channel subunits underlying the neuronal M-current have been associated with infantile-onset epileptic disorders. The clinical spectrum ranges from self-limited neonatal seizures to epileptic encephalopathy and delayed development. Mutations in KCNQ2 could be either gain- or loss-of-function which require different therapeutic approaches. To better understand genotype–phenotype correlation, more reports of patients and their mutations with elucidated molecular mechanism are needed. We studied 104 patients with infantile-onset pharmacoresistant epilepsy who underwent exome or genome sequencing. Nine patients with neonatal-onset seizures from unrelated families were found to harbor pathogenic or likely pathogenic variants in the KCNQ2 gene. The p.(N258K) was recently reported, and p. (G279D) has never been previously reported. Functional effect of p.(N258K) and p.(G279D) has never been previously studied. The cellular localization study ...
A potassium channel mutation in neonatal human epilepsy
1998
Benign familial neonatal convulsions (BFNC) is an autosomal dominant epilepsy of infancy, with loci mapped to human chromosomes 20q13.3 and 8q24. By positional cloning, a potassium channel gene (KCNQ2) located on 20q13.3 was isolated and found to be expressed in brain. Expression of KCNQ2 in frog (Xenopus laevis) oocytes led to potassium-selective currents that activated slowly with depolarization. In a large pedigree with BFNC, a five-base pair insertion would delete more than 300 amino acids from the KCNQ2 carboxyl terminus. Expression of the mutant channel did not yield measurable currents. Thus, impairment of potassium-dependent repolarization is likely to cause this age-specific epileptic syndrome.