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Musculoskeletal features without ataxia associated with a novel de novo mutation in KCNA1 impairing the voltage sensitivity of Kv1.1 channel

Authors :
Maria Cristina D'Adamo
Paola Imbrici
Concetta Altamura
Stefano Gustincich
Chiara Fiorillo
Stella Vari
Anna Allegri
Matteo Cataldi
Noemi Brolatti
Federico Zara
Jean-François Desaphy
Michele Iacomino
Marina Pedemonte
Rikard Blunck
Andrea Accogli
Valeria Capra
Source :
Biomedicines, Volume 9, Issue 1, Biomedicines, Vol 9, Iss 75, p 75 (2021)
Publication Year :
2021
Publisher :
MDPI AG, 2021.

Abstract

The KCNA1 gene encodes the &alpha<br />subunit of the voltage-gated Kv1.1 potassium channel that critically regulates neuronal excitability in the central and peripheral nervous systems. Mutations in KCNA1 have been classically associated with episodic ataxia type 1 (EA1), a movement disorder triggered by physical and emotional stress. Additional features variably reported in recent years include epilepsy, myokymia, migraine, paroxysmal dyskinesia, hyperthermia, hypomagnesemia, and cataplexy. Interestingly, a few individuals with neuromyotonia, either isolated or associated with skeletal deformities, have been reported carrying variants in the S2&ndash<br />S3 transmembrane segments of Kv1.1 channels in the absence of any other symptoms. Here, we have identified by whole-exome sequencing a novel de novo variant, T268K, in KCNA1 in a boy displaying recurrent episodes of neuromyotonia, muscle hypertrophy, and skeletal deformities. Through functional analysis in heterologous cells and structural modeling, we show that the mutation, located at the extracellular end of the S3 helix, causes deleterious effects, disrupting Kv1.1 function by altering the voltage dependence of activation and kinetics of deactivation, likely due to abnormal interactions with the voltage sensor in the S4 segment. Our study supports previous evidence suggesting that specific residues within the S2 and S3 segments of Kv1.1 result in a distinctive phenotype with predominant musculoskeletal presentation.

Details

Language :
English
Database :
OpenAIRE
Journal :
Biomedicines, Volume 9, Issue 1, Biomedicines, Vol 9, Iss 75, p 75 (2021)
Accession number :
edsair.doi.dedup.....c6b3252a9594b2dbf5ecffd316e01324