Abstract:This is an open access article under the terms of the Creat ive Commo ns Attri bution-NonCo mmercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
“…Thus, replacing proline residues in the PVP region affects S6 flexibility and pore opening and leads to drastically reduced channel activity (LoF defect). Indeed, Kv1.1 P403S and P405L channels failed to generate measurable currents when expressed in CHO cells, whereas the P403A and P405S channels showed a marked depolarizing shift in voltage-dependent activation and a significant reduction in current density [ 18 ]. In addition, the P403A subunit exerts a clear dominant-negative effect on the wild-type Kv1.1 subunit, further lowering potassium flow.…”
Section: Discussionmentioning
confidence: 99%
“…This is not surprising if one considers that kcna1 knock out mice have increased seizures susceptibility and undergo premature death (SUDEP) [ 14 ]. Since 2018, at least four mutations in the pore domain of Kv1.1 channel have been described in patients with early onset developmental and epileptic encephalopathy (DEE) [ 15 , 16 , 17 , 18 ]. Three of these mutations alter the two proline residues in the Pro-Val-Pro (PVP) motif at the C-terminal end of S6 (P403S, P405S, P405L), whereas the fourth is located close to the selectivity filter for potassium ions in the S5–S6 loop (V368L).…”
Mutations in the KCNA1 gene, encoding the voltage-gated potassium channel Kv1.1, have been associated with a spectrum of neurological phenotypes, including episodic ataxia type 1 and developmental and epileptic encephalopathy. We have recently identified a de novo variant in KCNA1 in the highly conserved Pro-Val-Pro motif within the pore of the Kv1.1 channel in a girl affected by early onset epilepsy, ataxia and developmental delay. Other mutations causing severe epilepsy are located in Kv1.1 pore domain. The patient was initially treated with a combination of antiepileptic drugs with limited benefit. Finally, seizures and ataxia control were achieved with lacosamide and acetazolamide. The aim of this study was to functionally characterize Kv1.1 mutant channel to provide a genotype–phenotype correlation and discuss therapeutic options for KCNA1-related epilepsy. To this aim, we transfected HEK 293 cells with Kv1.1 or P403A cDNAs and recorded potassium currents through whole-cell patch-clamp. P403A channels showed smaller potassium currents, voltage-dependent activation shifted by +30 mV towards positive potentials and slower kinetics of activation compared with Kv1.1 wild-type. Heteromeric Kv1.1+P403A channels, resembling the condition of the heterozygous patient, confirmed a loss-of-function biophysical phenotype. Overall, the functional characterization of P403A channels correlates with the clinical symptoms of the patient and supports the observation that mutations associated with severe epileptic phenotype cluster in a highly conserved stretch of residues in Kv1.1 pore domain. This study also strengthens the beneficial effect of acetazolamide and sodium channel blockers in KCNA1 channelopathies.
“…Thus, replacing proline residues in the PVP region affects S6 flexibility and pore opening and leads to drastically reduced channel activity (LoF defect). Indeed, Kv1.1 P403S and P405L channels failed to generate measurable currents when expressed in CHO cells, whereas the P403A and P405S channels showed a marked depolarizing shift in voltage-dependent activation and a significant reduction in current density [ 18 ]. In addition, the P403A subunit exerts a clear dominant-negative effect on the wild-type Kv1.1 subunit, further lowering potassium flow.…”
Section: Discussionmentioning
confidence: 99%
“…This is not surprising if one considers that kcna1 knock out mice have increased seizures susceptibility and undergo premature death (SUDEP) [ 14 ]. Since 2018, at least four mutations in the pore domain of Kv1.1 channel have been described in patients with early onset developmental and epileptic encephalopathy (DEE) [ 15 , 16 , 17 , 18 ]. Three of these mutations alter the two proline residues in the Pro-Val-Pro (PVP) motif at the C-terminal end of S6 (P403S, P405S, P405L), whereas the fourth is located close to the selectivity filter for potassium ions in the S5–S6 loop (V368L).…”
Mutations in the KCNA1 gene, encoding the voltage-gated potassium channel Kv1.1, have been associated with a spectrum of neurological phenotypes, including episodic ataxia type 1 and developmental and epileptic encephalopathy. We have recently identified a de novo variant in KCNA1 in the highly conserved Pro-Val-Pro motif within the pore of the Kv1.1 channel in a girl affected by early onset epilepsy, ataxia and developmental delay. Other mutations causing severe epilepsy are located in Kv1.1 pore domain. The patient was initially treated with a combination of antiepileptic drugs with limited benefit. Finally, seizures and ataxia control were achieved with lacosamide and acetazolamide. The aim of this study was to functionally characterize Kv1.1 mutant channel to provide a genotype–phenotype correlation and discuss therapeutic options for KCNA1-related epilepsy. To this aim, we transfected HEK 293 cells with Kv1.1 or P403A cDNAs and recorded potassium currents through whole-cell patch-clamp. P403A channels showed smaller potassium currents, voltage-dependent activation shifted by +30 mV towards positive potentials and slower kinetics of activation compared with Kv1.1 wild-type. Heteromeric Kv1.1+P403A channels, resembling the condition of the heterozygous patient, confirmed a loss-of-function biophysical phenotype. Overall, the functional characterization of P403A channels correlates with the clinical symptoms of the patient and supports the observation that mutations associated with severe epileptic phenotype cluster in a highly conserved stretch of residues in Kv1.1 pore domain. This study also strengthens the beneficial effect of acetazolamide and sodium channel blockers in KCNA1 channelopathies.
“…described four heterozygous de novo variants in KCNA1: P403S, P405L, P405S and A261T. 34 Our MTL-SVM correctly predicted three out of four variants with high confidence ( Figure 3 a). The A261T variant, which resulted in a hyperpolarizing shift of the voltage-dependence of activation (GOF), was incorrectly predicted as LOF.…”
Section: Resultsmentioning
confidence: 77%
“…For both use cases presented here ( KCNA1, KCNA2 ), possible precision therapies based on variant function have been proposed. 15 , 34 , 35 Figure 3 Radar plots of class probability distributions for each variant, with class probabilities shown in the legend. a: KCNA1 p.P403S was correctly predicted as LOF (P405L and P405S are not shown).…”
“…The observation that both GoF and LoF variants in the same ion channel gene can cause disorders with apparently similar clinical characteristics (such as epilepsy and neurodevelopmental delay) is the rule rather than the exception. [14][15][16] For KCNMA1-linked diseases, while LoF variants may slow the repolarization process and prolong the action potential duration, thereby increasing presynaptic Ca 2+ influx and neurotransmitter release, 17 GoF variants, by accelerating action potential repolarization, may speed Na + channels recovery from inactivation and allow neurons to fire at a faster rate.…”
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