Key result
A novel de novo T268K variant in KCNA1 disrupted Kv1.1 channel function by altering voltage dependence of activation and deactivation kinetics, leading to a predominant musculoskeletal phenotype.
Case Report (n=1)
The identification of the T268K mutation in KCNA1 expands the phenotypic spectrum of Kv1.1 channelopathies to include predominant musculoskeletal features without ataxia.
Alerts clinicians to KCNA1 variants in isolated musculoskeletal presentations; extends phenotypic spectrum but remains hypothesis-generating.
The KCNA1 gene encodes the α 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–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.
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Imbrici et al. (2021) conducted a case report in Neuromyotonia, muscle hypertrophy, and skeletal deformities (n=1). T268K variant in KCNA1 was evaluated on Functional effects of the T268K mutation on Kv1.1 channel. A novel de novo T268K variant in KCNA1 disrupted Kv1.1 channel function by altering voltage dependence of activation and deactivation kinetics, leading to a predominant musculoskeletal phenotype.
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