ArticleNeurobiology of disease2016
Single amino acid deletion in transmembrane segment D4S6 of sodium channel Scn8a (Nav1.6) in a mouse mutant with a chronic movement disorder.
Article in Neurobiology of disease, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 30 citations in OpenAlex.
- Voltage-gated sodium channels in the nervous system: Molecular physiology to therapeutic interventions.Neural regeneration research · 2026Article
- Distinct neuronal mechanisms for motor impairment and seizures in a novel mouse model of SCN8A epileptic encephalopathy.Neurobiology of disease · 2026Article
- Tsc1 deletion in Purkinje neurons disrupts the axon initial segment, impairing excitability and cerebellar function.Neurobiology of disease · 2025Article
- Allele-Specific Editing of a Dominant SCN8A Epilepsy Variant Protects against Seizures and Lethality in a Murine Model.Annals of neurology · 2024Article
- Optimizing Nav1.7-Targeted Analgesics: Revealing Off-Target Effects of Spider Venom-Derived Peptide Toxins and Engineering Strategies for Improvement.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Article
- Structure of human NaNature communications · 2023Article
- Clinical and Functional Features of Epilepsy-Associated In-Frame Deletion Variants inFrontiers in molecular neuroscience · 2022Article
- Sodium channelopathies of skeletal muscle and brain.Physiological reviews · 2021Review
- Review
- Sodium channelopathies in neurodevelopmental disorders.Nature reviews. Neuroscience · 2021Review
- Pathogenic in-Frame Variants inFrontiers in pharmacology · 2021Article
- Trafficking mechanisms underlying NaChannels (Austin, Tex.) · 2020Review
- Engineering Herbicide-Tolerance Rice Expressing an Acetohydroxyacid Synthase with a Single Amino Acid Deletion.International journal of molecular sciences · 2020Article
- Molecular Mechanisms and Therapeutics for Spinocerebellar Ataxia Type 2.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2019Review
- Partial loss-of-function of sodium channel SCN8A in familial isolated myoclonus.Human mutation · 2018Article
- Animal Models of Tremor: Relevance to Human Tremor Disorders.Tremor and other hyperkinetic movements (New York, N.Y.) · 2018Review
- Using the shared genetics of dystonia and ataxia to unravel their pathogenesis.Neuroscience and biobehavioral reviews · 2017Review
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Authors and funding
14 authors at 4 institutions in 1 country.
Funding
Abstract
Mutations of the neuronal sodium channel gene SCN8A are associated with lethal movement disorders in the mouse and with human epileptic encephalopathy. We describe a spontaneous mouse mutation, Scn8a(9J), that is associated with a chronic movement disorder with early onset tremor and adult onset dystonia. Scn8a(9J) homozygotes have a shortened lifespan, with only 50% of mutants surviving beyond 6 months of age. The 3 bp in-frame deletion removes 1 of the 3 adjacent isoleucine residues in transmembrane segment DIVS6 of Nav1.6 (p.Ile1750del). The altered helical orientation of the transmembrane segment displaces pore-lining amino acids with important roles in channel activation and inactivation. The predicted impact on channel activity was confirmed by analysis of cerebellar Purkinje neurons from mutant mice, which lack spontaneous and induced repetitive firing. In a heterologous expression system, the activity of the mutant channel was below the threshold for detection. Observations of decreased nerve conduction velocity and impaired behavior in an open field are also consistent with reduced activity of Nav1.6. The Nav1.6Δ1750 protein is only partially glycosylated. The abundance of mutant Nav1.6 is reduced at nodes of Ranvier and is not detectable at the axon initial segment. Despite a severe reduction in channel activity, the lifespan and motor function of Scn8a(9J/9J) mice are significantly better than null mutants lacking channel protein. The clinical phenotype of this severe hypomorphic mutant expands the spectrum of Scn8a disease to include a recessively inherited, chronic and progressive movement disorder.
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Registered trials
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.