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A Kv7.2 mutation associated with early onset epileptic encephalopathy with suppression-burst enhances Kv7/M channel activity
- Source :
- Epilepsia, Epilepsia, Wiley, 2016, 57 (5), pp.e87-e93. ⟨10.1111/epi.13366⟩, Epilepsia, 2016, 57 (5), pp.e87-e93. ⟨10.1111/epi.13366⟩
- Publication Year :
- 2016
- Publisher :
- Wiley, 2016.
-
Abstract
- International audience; Mutations in the KCNQ2 gene encoding the voltage-gated potassium channel subunit Kv7.2 cause early onset epileptic encephalopathy (EOEE). Most mutations have been shown to induce a loss of function or to affect the subcellular distribution of Kv7 channels in neurons. Herein, we investigated functional consequences and subcellular distribution of the p.V175L mutation of Kv7.2 (Kv7.2 V175L) found in a patient presenting EOEE. We observed that the mutation produced a 25–40 mV hyperpolarizing shift of the conductance–voltage relationship of both the homomeric Kv7.2 V175L and hetero-meric Kv7.2 V175L /Kv7.3 channels compared to wild-type channels and a 10 mV hyper-polarizing shift of Kv7.2 V175L /Kv7.2/Kv7.3 channels in a 1:1:2 ratio mimicking the patient situation. Mutant channels also displayed faster activation kinetics and an increased current density that was prevented by 1 lM linopirdine. The p.V175L mutation did not affect the protein expression of Kv7 channels and its localization at the axon initial segment. We conclude that p.V175L is a gain of function mutation. This confirms previous observations showing that mutations having opposite consequences on M channels can produce EOEE. These findings alert us that drugs aiming to increase Kv7 channel activity might have adverse effects in EOEE in the case of gain-of-function variants.
- Subjects :
- Male
0301 basic medicine
Indoles
Patch-Clamp Techniques
Pyridines
[SDV]Life Sciences [q-bio]
[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology
[SDV.GEN] Life Sciences [q-bio]/Genetics
Phenylenediamines
medicine.disease_cause
Hippocampus
Linopirdine
Membrane Potentials
0302 clinical medicine
KCNQ2 Potassium Channel
[SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB]
M-current
ComputingMilieux_MISCELLANEOUS
Neurons
KCNQ2
Membrane potential
Mutation
[SDV.MHEP] Life Sciences [q-bio]/Human health and pathology
Axon initial segment
Potassium channel
Cell biology
[SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology
Neurology
Anticonvulsants
Female
[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]
Spasms, Infantile
medicine.drug
Ankyrins
CHO Cells
Biology
Polymorphism, Single Nucleotide
03 medical and health sciences
Cricetulus
Potassium Channel Blockers
medicine
Animals
Humans
[SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]
Patch clamp
[SDV.GEN]Life Sciences [q-bio]/Genetics
Potassium channel blocker
Early onset epileptic encephalopathy
Electric Stimulation
030104 developmental biology
Gain of function
Carbamates
Neurology (clinical)
Neuroscience
[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
030217 neurology & neurosurgery
Subjects
Details
- ISSN :
- 00139580
- Volume :
- 57
- Database :
- OpenAIRE
- Journal :
- Epilepsia
- Accession number :
- edsair.doi.dedup.....1bc6e5cb14f9a38eda1d700774fe1d5e