Case report: A novel loss-of-function pathogenic variant in the KCNA1 cytoplasmic N-terminus causing carbamazepine-responsive type 1 episodic ataxia

Manville, Rían W.; Sidlow, Richard; Abbott, Geoffrey W.

doi:10.3389/fneur.2022.975849

Cited by 6 publications

(8 citation statements)

References 19 publications

(23 reference statements)

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“…The newly found variant in S1 is a V174A mutation, which is the same location as a different previously described EA1 mutation (V174F) [1,8,9]. Additionally, a patient was identified with EA1 due to an L155P mutation that is noteworthy because it is one of only three pathogenic variants ever found to affect the Nterminus of the protein [5]. The other two were also recently discovered and they are associated with musculoskeletal abnormalities, as discussed below.…”

Section: Episodic Ataxia Type 1 (Ea1) Mutationsmentioning

confidence: 57%

“…The N-terminal domain has been hypothesized to be important for regulating subunit assembly [74]. Electrophysiological studies of the human L155P mutation showed that outward K + currents are eliminated in homomeric mutant channels demonstrating they are non-functional [5]. Furthermore, channels composed of 50/50 combinations of wildtype and L155P subunits exhibit peak currents that are reduced by more than half and altered gating kinetics with several-fold faster inactivation [5].…”

Section: Musculoskeletal Abnormalitiesmentioning

confidence: 99%

“…Electrophysiological studies of the human L155P mutation showed that outward K + currents are eliminated in homomeric mutant channels demonstrating they are non-functional [5]. Furthermore, channels composed of 50/50 combinations of wildtype and L155P subunits exhibit peak currents that are reduced by more than half and altered gating kinetics with several-fold faster inactivation [5]. Previously, the lack of pathogenic variants in the N-terminal region suggested that mutations there were likely benign (i.e., not disease causing) and consequently never clinically identified.…”

Section: Musculoskeletal Abnormalitiesmentioning

confidence: 99%

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Novel Genetic Variants Expand the Functional, Molecular and Pathological Diversity of KCNA1 Channelopathy

Paulhus¹,

Glasscock²

2023

Preprint

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The KCNA1 gene encodes Kv1.1 voltage-gated potassium channel α subunits, which are crucial for maintaining healthy neuronal firing and preventing hyperexcitability. Mutations in the KCNA1 gene can cause several neurological diseases and symptoms, such as episodic ataxia and epilepsy, which may occur alone or in combination, making it challenging to establish simple genotype-phenotype correlations. Previous analyses of human KCNA1 variants have shown that epilepsy-linked mutations tend to cluster in regions critical for the channel’s pore, whereas EA1-associated mutations are evenly distributed across the length of the protein. In this review, we examine 17 recently discovered pathogenic or likely pathogenic KCNA1 variants to gain new insights into the molecular genetic basis of KCNA1 channelopathy. We provide the first systematic breakdown of disease rates for KCNA1 variants in different protein domains, uncovering potential location biases that influence genotype-phenotype correlations. Our examination of the new mutations strengthens the proposed link between the pore region and epilepsy and reveals new connections between epilepsy-related variants, genetic modifiers, and respiratory dysfunction. Additionally, the new variants include the first two gain-of-function mutations ever discovered for KCNA1, the first frameshift mutation, and the first mutations located in the cytoplasmic N-terminal domain, broadening the functional and molecular scope of KCNA1 channelopathy. Moreover, the recently identified variants highlight emerging links between KCNA1 and musculoskeletal abnormalities and nystagmus, conditions not typically associated with KCNA1. These findings improve our understanding of KCNA1 channelopathy and promise to enhance personalized diagnosis and treatment for individuals with KCNA1-linked disorders.

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Section: Episodic Ataxia Type 1 (Ea1) Mutationsmentioning

confidence: 57%

Section: Musculoskeletal Abnormalitiesmentioning

confidence: 99%

Section: Musculoskeletal Abnormalitiesmentioning

confidence: 99%

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Novel Genetic Variants Expand the Functional, Molecular and Pathological Diversity of KCNA1 Channelopathy

Paulhus¹,

Glasscock²

2023

Preprint

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“…5a ). We recently demonstrated that L155P eradicates activity in 100% mutant channels and non-dominantly impairs activity in wild-type Kv1.1/Kv1.1-L155P channels generated from co-injection in oocytes of 50/50 wild-type/L155P Kv1.1 cRNA (hereafter referred to as “Kv1.1/Kv1.1-L155P” channels 42 . When applied to 100% Kv1.1-L155P channels (hereafter referred to as “Kv1.1-L155P” channels, the extracts were unable to rescue activity (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Native American ataxia medicines rescue ataxia-linked mutant potassium channel activity via binding to the voltage sensing domain

et al. 2023

Self Cite

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There are currently no drugs known to rescue the function of Kv1.1 voltage-gated potassium channels carrying loss-of-function sequence variants underlying the inherited movement disorder, Episodic Ataxia 1 (EA1). The Kwakwaka’wakw First Nations of the Pacific Northwest Coast used Fucus gardneri (bladderwrack kelp), Physocarpus capitatus (Pacific ninebark) and Urtica dioica (common nettle) to treat locomotor ataxia. Here, we show that extracts of these plants enhance wild-type Kv1.1 current, especially at subthreshold potentials. Screening of their constituents revealed that gallic acid and tannic acid similarly augment wild-type Kv1.1 current, with submicromolar potency. Crucially, the extracts and their constituents also enhance activity of Kv1.1 channels containing EA1-linked sequence variants. Molecular dynamics simulations reveal that gallic acid augments Kv1.1 activity via a small-molecule binding site in the extracellular S1-S2 linker. Thus, traditional Native American ataxia treatments utilize a molecular mechanistic foundation that can inform small-molecule approaches to therapeutically correcting EA1 and potentially other Kv1.1-linked channelopathies.

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“…It has also been observed that individuals with KCNA1 variants at the C-terminus are more likely to suffer from seizures and developmental delay than those with variants at the N-terminus. 83 , 84 …”

Section: Channelopathiesmentioning

confidence: 99%

Genetic Links to Episodic Movement Disorders: Current Insights

Garg¹,

Mohammad²,

Shukla³

et al. 2023

TACG

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Episodic or paroxysmal movement disorders (PxMD) are conditions, which occur episodically, are transient, usually have normal interictal periods, and are characterized by hyperkinetic disorders, including ataxia, chorea, dystonia, and ballism. Broadly, these comprise paroxysmal dyskinesias (paroxysmal kinesigenic and non-kinesigenic dyskinesia [PKD/PNKD], paroxysmal exercise-induced dyskinesias [PED]) and episodic ataxias (EA) types 1–9. Classification of paroxysmal dyskinesias has traditionally been clinical. However, with advancement in genetics and the discovery of the molecular basis of several of these disorders, it is becoming clear that phenotypic pleiotropy exists, that is, the same variant may give rise to a variety of phenotypes, and the classical understanding of these disorders requires a new paradigm. Based on molecular pathogenesis, paroxysmal disorders are now categorized as synaptopathies, transportopathies, channelopathies, second-messenger related disorders, mitochondrial or others. A genetic paradigm also has an advantage of identifying potentially treatable disorders, such as glucose transporter 1 deficiency syndromes, which necessitates a ketogenic diet, and ADCY5 -related disorders, which may respond to caffeine. Clues for a primary etiology include age at onset below 18 years, presence of family history and fixed triggers and attack duration. Paroxysmal movement disorder is a network disorder, with both the basal ganglia and the cerebellum implicated in pathogenesis. Abnormalities in the striatal cAMP turnover pathway may also be contributory. Although next-generation sequencing has restructured the approach to paroxysmal movement disorders, the genetic underpinnings of several entities remain undiscovered. As more genes and variants continue to be reported, these will lead to enhanced understanding of pathophysiological mechanisms and precise treatment.

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Case report: A novel loss-of-function pathogenic variant in the KCNA1 cytoplasmic N-terminus causing carbamazepine-responsive type 1 episodic ataxia

Cited by 6 publications

References 19 publications

Novel Genetic Variants Expand the Functional, Molecular and Pathological Diversity of KCNA1 Channelopathy

Novel Genetic Variants Expand the Functional, Molecular and Pathological Diversity of KCNA1 Channelopathy

Native American ataxia medicines rescue ataxia-linked mutant potassium channel activity via binding to the voltage sensing domain

Genetic Links to Episodic Movement Disorders: Current Insights

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