ArticleThe Journal of physiology2012
Altered Kv3.3 channel gating in early-onset spinocerebellar ataxia type 13.
Article in The Journal of physiology, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 45 citations in OpenAlex.
- A novel early onset spinocerebellar ataxia 13 BAC mouse model with cerebellar atrophy, tremor, and ataxic gait.Experimental animals · 2025Article
- Potential Benefit of Channel Activators in Loss-of-Function Primary Potassium Channelopathies Causing Heredoataxia.Cerebellum (London, England) · 2024Review
- A structurally precise mechanism links an epilepsy-associatedProceedings of the National Academy of Sciences of the United States of America · 2024Article
- Voltage-gated potassium channels as a potential therapeutic target for the treatment of neurological and psychiatric disorders.Frontiers in cellular neuroscience · 2024Review
- Epilepsy as the symptom of a spinocerebellar ataxia 13 in a patient presenting with a mutation in the KCNC3 gene.BMC neurology · 2023Article
- Spontaneous seizure and memory loss in mice expressing an epileptic encephalopathy variant in the calmodulin-binding domain of KProceedings of the National Academy of Sciences of the United States of America · 2021Article
- Suppression of Kv3.3 channels by antisense oligonucleotides reverses biochemical effects and motor impairment in spinocerebellar ataxia type 13 mice.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2021Article
- Rare Gain-of-FunctionInternational journal of molecular sciences · 2021Article
- Article
- Cerebellar Kv3.3 potassium channels activate TANK-binding kinase 1 to regulate trafficking of the cell survival protein Hax-1.Nature communications · 2021Article
- Presynaptic Kv3 channels are required for fast and slow endocytosis of synaptic vesicles.Neuron · 2021Article
- Article
- Determining the correct stoichiometry of Kv2.1/Kv6.4 heterotetramers, functional in multiple stoichiometrical configurations.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Epileptic Encephalopathy In A Patient With A Novel Variant In The Kv7.2 S2 Transmembrane Segment: Clinical, Genetic, and Functional Features.International journal of molecular sciences · 2019Article
- Encephalopathies with KCNC1 variants: genotype-phenotype-functional correlations.Annals of clinical and translational neurology · 2019Article
- Modeling Neurodegenerative Spinocerebellar Ataxia Type 13 in Zebrafish Using a Purkinje Neuron Specific Tunable Coexpression System.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2019Article
- Neurological Disease Modelling for Spinocerebellar Ataxia Using Zebrafish.Journal of experimental neuroscience · 2019Article
- Novel Features and Abnormal Pattern of Cerebral Glucose Metabolism in Spinocerebellar Ataxia 19.Cerebellum (London, England) · 2018Article
- Kv4.2 autism and epilepsy mutation enhances inactivation of closed channels but impairs access to inactivated state after opening.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Kv3 Channels: Enablers of Rapid Firing, Neurotransmitter Release, and Neuronal Endurance.Physiological reviews · 2017Review
Corrections and comments
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Authors and funding
3 authors at 1 institution in 2 countries.
Funding
Abstract
Mutations in Kv3.3 cause spinocerebellar ataxia type 13 (SCA13). Depending on the causative mutation, SCA13 is either a neurodevelopmental disorder that is evident in infancy or a progressive neurodegenerative disease that emerges during adulthood. Previous studies did not clarify the relationship between these distinct clinical phenotypes and the effects of SCA13 mutations on Kv3.3 function. The F448L mutation alters channel gating and causes early-onset SCA13. R420H and R423H suppress Kv3 current amplitude by a dominant negative mechanism. However, R420H results in the adult form of the disease whereas R423H produces the early-onset, neurodevelopmental form with significant clinical overlap with F448L. Since individuals with SCA13 have one wild type and one mutant allele of the Kv3.3 gene, we analysed the properties of tetrameric channels formed by mixtures of wild type and mutant subunits. We report that one R420H subunit and at least one R423H subunit can co-assemble with the wild type protein to form active channels. The functional properties of channels containing R420H and wild type subunits strongly resemble those of wild type alone. In contrast, channels containing R423H and wild type subunits show significantly altered gating, including a hyperpolarized shift in the voltage dependence of activation, slower activation, and modestly slower deactivation. Notably, these effects resemble the modified gating seen in channels containing a mixture of F448L and wild type subunits, although the F448L subunit slows deactivation more dramatically than the R423H subunit. Our results suggest that the clinical severity of R423H reflects its dual dominant negative and dominant gain of function effects. However, as shown by R420H, reducing current amplitude without altering gating does not result in infant onset disease. Therefore, our data strongly suggest that changes in Kv3.3 gating contribute significantly to an early age of onset in SCA13.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.