Identification of a New de Novo Mutation Underlying Regressive Episodic Ataxia Type I

Karalök, Zeynep Selen; Megaro, Alfredo; Cenciarini, Marta; Güven, Alev; Hasan, Sonia; Taskin, Birce Dilge; Imbrici, Paola; Ceylaner, Serdar; Pessia, Mauro; D’Adamo, Maria Cristina

doi:10.3389/fneur.2018.00587

Cited by 9 publications

(8 citation statements)

References 31 publications

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“…Many of these mutations have been examined at the electrophysiological level to determine their functional consequences. These studies provide evidence that pathological KCNA1 mutations lead to a loss-of-function (LOF) of Kv1.1 by various mechanisms [18,35]. Furthermore, some KCNA1 mutations have a dominant negative effect whereby incorporation of the mutated α-subunit detrimentally impacts the otherwise normal subunits that form the tetrameric structure of the potassium channel [37,39].…”

Section: Overview Of Kcna1 Mutations In Ea1 and Diseasementioning

confidence: 94%

Clinical Spectrum of KCNA1 Mutations: New Insights into Episodic Ataxia and Epilepsy Comorbidity

Paulhus

Ammerman

Glasscock

2020

IJMS

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Mutations in the KCNA1 gene, which encodes voltage-gated Kv1.1 potassium channel α-subunits, cause a variety of human diseases, complicating simple genotype–phenotype correlations in patients. KCNA1 mutations are primarily associated with a rare neurological movement disorder known as episodic ataxia type 1 (EA1). However, some patients have EA1 in combination with epilepsy, whereas others have epilepsy alone. KCNA1 mutations can also cause hypomagnesemia and paroxysmal dyskinesia in rare cases. Why KCNA1 variants are associated with such phenotypic heterogeneity in patients is not yet understood. In this review, literature databases (PubMed) and public genetic archives (dbSNP and ClinVar) were mined for known pathogenic or likely pathogenic mutations in KCNA1 to examine whether patterns exist between mutation type and disease manifestation. Analyses of the 47 deleterious KCNA1 mutations that were identified revealed that epilepsy or seizure-related variants tend to cluster in the S1/S2 transmembrane domains and in the pore region of Kv1.1, whereas EA1-associated variants occur along the whole length of the protein. In addition, insights from animal models of KCNA1 channelopathy were considered, as well as the possible influence of genetic modifiers on disease expressivity and severity. Elucidation of the complex relationship between KCNA1 variants and disease will enable better diagnostic risk assessment and more personalized therapeutic strategies for KCNA1 channelopathy.

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Section: Overview Of Kcna1 Mutations In Ea1 and Diseasementioning

confidence: 94%

Clinical Spectrum of KCNA1 Mutations: New Insights into Episodic Ataxia and Epilepsy Comorbidity

Paulhus

Ammerman

Glasscock

2020

IJMS

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“…Kv channels in the nervous system are mainly composed of Kv1.1, Kv1.2 and Kv1.4 subunits, which coassemble into homotetrameric or heterotetrameric channels. Described KCNA1 mutations result mostly in variable loss-of-function effects of the Kv1.1 channel, mainly classified into: (i) an impairment in protein expression, assembly or trafficking to the cell membrane or (ii) alterations in channel function, such as reduced channel conductance, shifts in voltage-dependent activation or altered kinetics 2 16 17. Interestingly, given the heteromeric nature of potassium channels, mutated Kv1.1 subunits can alter the function of other subunits 2.…”

Section: Introductionmentioning

confidence: 99%

Complete loss of KCNA1 activity causes neonatal epileptic encephalopathy and dyskinesia

et al. 2019

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BackgroundSince 1994, over 50 families affected by the episodic ataxia type 1 disease spectrum have been described with mutations in KCNA1, encoding the voltage-gated K+ channel subunit Kv1.1. All of these mutations are either transmitted in an autosomal-dominant mode or found as de novo events.MethodsA patient presenting with a severe combination of dyskinesia and neonatal epileptic encephalopathy was sequenced by whole-exome sequencing (WES). A candidate variant was tested using cellular assays and patch-clamp recordings.ResultsWES revealed a homozygous variant (p.Val368Leu) in KCNA1, involving a conserved residue in the pore domain, close to the selectivity signature sequence for K+ ions (TVGYG). Functional analysis showed that mutant protein alone failed to produce functional channels in homozygous state, while coexpression with wild-type produced no effects on K+ currents, similar to wild-type protein alone. Treatment with oxcarbazepine, a sodium channel blocker, proved effective in controlling seizures.ConclusionThis newly identified variant is the first to be reported to act in a recessive mode of inheritance in KCNA1. These findings serve as a cautionary tale for the diagnosis of channelopathies, in which an unreported phenotypic presentation or mode of inheritance for the variant of interest can hinder the identification of causative variants and adequate treatment choice.

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“…Importantly, patients with episodic ataxia type 1 are more likely to have seizures than the general population, strongly implicating mutations in this gene as a cause of epilepsy, as further discussed below (A242P in [57]; T226R in [66]; V408L in [51,56]). In a single case, amelioration of mild EA1 symptoms with age and therapy discontinuation have been reported (G311D in [67]). Recently, two KCNA1 mutations have been identified in families with paroxysmal kinesigenic dyskinesia (N255K and L319R in [68]).…”

Section: Clinical Aspects and Therapeutic Management Of Episodic Ataxmentioning

confidence: 97%

“…Recently, two KCNA1 mutations have been identified in families with paroxysmal kinesigenic dyskinesia (N255K and L319R in [68]). Despite being an autosomal dominantly inherited disease in the majority of cases, EA1 may also occur as a result of de novo mutation (G311D in [67]; I262M in [69]). Therefore, for a correct EA1 diagnosis, molecular genetic testing of KCNA1 is recommended even in the absence of family history, if EA1-like symptoms are present.…”

Section: Clinical Aspects and Therapeutic Management Of Episodic Ataxmentioning

confidence: 99%

Kv1.1 Channelopathies: Pathophysiological Mechanisms and Therapeutic Approaches

D’Adamo

Liantonio

Rolland

et al. 2020

IJMS

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Kv1.1 belongs to the Shaker subfamily of voltage-gated potassium channels and acts as a critical regulator of neuronal excitability in the central and peripheral nervous systems. KCNA1 is the only gene that has been associated with episodic ataxia type 1 (EA1), an autosomal dominant disorder characterized by ataxia and myokymia and for which different and variable phenotypes have now been reported. The iterative characterization of channel defects at the molecular, network, and organismal levels contributed to elucidating the functional consequences of KCNA1 mutations and to demonstrate that ataxic attacks and neuromyotonia result from cerebellum and motor nerve alterations. Dysfunctions of the Kv1.1 channel have been also associated with epilepsy and kcna1 knock-out mouse is considered a model of sudden unexpected death in epilepsy. The tissue-specific association of Kv1.1 with other Kv1 members, auxiliary and interacting subunits amplifies Kv1.1 physiological roles and expands the pathogenesis of Kv1.1-associated diseases. In line with the current knowledge, Kv1.1 has been proposed as a novel and promising target for the treatment of brain disorders characterized by hyperexcitability, in the attempt to overcome limited response and side effects of available therapies. This review recounts past and current studies clarifying the roles of Kv1.1 in and beyond the nervous system and its contribution to EA1 and seizure susceptibility as well as its wide pharmacological potential.

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Identification of a New de Novo Mutation Underlying Regressive Episodic Ataxia Type I

Cited by 9 publications

References 31 publications

Clinical Spectrum of KCNA1 Mutations: New Insights into Episodic Ataxia and Epilepsy Comorbidity

Clinical Spectrum of KCNA1 Mutations: New Insights into Episodic Ataxia and Epilepsy Comorbidity

Complete loss of KCNA1 activity causes neonatal epileptic encephalopathy and dyskinesia

Kv1.1 Channelopathies: Pathophysiological Mechanisms and Therapeutic Approaches

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