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. 2022 Jan;63(1):e7-e14.
doi: 10.1111/epi.17118. Epub 2021 Nov 14.

Distinct epilepsy phenotypes and response to drugs in KCNA1 gain- and loss-of function variants

Francesco Miceli  1 , Renzo Guerrini  2 , Mario Nappi  1 , Maria Virginia Soldovieri  3 , Elena Cellini  2 , Christina A Gurnett  4 , Lucio Parmeggiani  5 , Davide Mei  2 , Maurizio Taglialatela  1
Affiliations

Distinct epilepsy phenotypes and response to drugs in KCNA1 gain- and loss-of function variants

Francesco Miceli et al. Epilepsia. 2022 Jan.

Abstract

A wide phenotypic spectrum of neurological diseases is associated with KCNA1 (Kv1.1) variants. To investigate the molecular basis of such a heterogeneous clinical presentation and identify the possible correlation with in vitro phenotypes, we compared the functional consequences of three heterozygous de novo variants (p.P403S, p.P405L, and p.P405S) in Kv1.1 pore region found in four patients with severe developmental and epileptic encephalopathy (DEE), with those of a de novo variant in the voltage sensor (p.A261T) identified in two patients with mild, carbamazepine-responsive, focal epilepsy. Patch-clamp electrophysiology was used to investigate the functional properties of mutant Kv1.1 subunits, both expressed as homomers and heteromers with wild-type Kv1.1 subunits. KCNA1 pore mutations markedly decreased (p. P405S) or fully suppressed (p. P403S, p. P405L) Kv1.1-mediated currents, exerting loss-of-function (LoF) effects. By contrast, channels carrying the p.A261T variant exhibited a hyperpolarizing shift of the activation process, consistent with a gain-of-function (GoF) effect. The present results unveil a novel correlation between in vitro phenotype (GoF vs LoF) and clinical course (mild vs severe) in KCNA1-related phenotypes. The excellent clinical response to carbamazepine observed in the patients carrying the A261T variant suggests an exquisite sensitivity of KCNA1 GoF to sodium channel inhibition that should be further explored.

Keywords: KCNA1; developmental encephalopathies; epilepsy; gain-of-function variants; loss-of-function variants; potassium channels.

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Conflict of interest statement

None of the authors has any conflict of interest to disclose. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

Figures

FIGURE 1
FIGURE 1
Location and functional characterization of Kv1.1 mutants. (A) Cartoon depicting the six transmembrane segments arrangement of a single Kv1.1 subunit (left panel) and sequence alignments of the S3 (top right panel) and S6 (lower right panel) region of Kv1.1, Kv1.2, and Kv2.1 subunits. (B) Macroscopic currents recorded from CHO cells transfected with plasmids encoding for wild‐type (WT) or the indicated mutant Kv1.1 subunits, in response to the voltage protocol shown below the Kv1.1 traces. Current scale, 500 pA; time scale, 40 ms. (C) Current density (expressed as pA/pF) at +20 mV from CHO cells expressing each of the indicated experimental group. Asterisks (*) indicate values significantly different from each respective control (p < .05). (D) Conductance/voltage curves for each of the indicated groups. Continuous lines are Boltzmann fits to the experimental data. Each data point is the mean ± SEM. of 13–21 cells recorded in at least three separate experimental sessions.
See this image and copyright information in PMC

References

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