期刊
EPILEPSIA
卷 63, 期 1, 页码 E7-E14出版社
WILEY
DOI: 10.1111/epi.17118
关键词
developmental encephalopathies; epilepsy; gain-of-function variants; KCNA1; loss-of-function variants; potassium channels
资金
- EU [N602531]
- Tuscany Region Call for Health 2018 (grant DECODE-EE)
- Federazione Italiana Epilessie
- Italian Ministry for University and Research (MIUR) [PRIN 2017ALCR7C, PRIN 2017YH3SXK]
- Italian Ministry of Health [RF-2019-12370491]
- European Commission [UNICOM -875299]
- European Joint Programme on Rare Disease JTC 2020 (TreatKCNQ)
This study compared the functional consequences of different KCNA1 gene variants in neurological diseases, revealing that pore mutations lead to loss-of-function effects, while voltage sensor mutations cause a hyperpolarizing shift in the activation process. There is a novel correlation between in vitro phenotypes (GoF vs LoF) and clinical presentation (mild vs severe).
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.
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