ArticleProceedings of the National Academy of Sciences of the United States of America2008
Divergent sodium channel defects in familial hemiplegic migraine.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers, 1 of them a synthesis that pooled it.
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Who cites it
51 citing papers in PubMed, 1 synthesis or guideline pooled it, 116 citations in OpenAlex.
- Gene variant effects across sodium channelopathies predict function and guide precision therapy.Brain : a journal of neurology · 2022Pooled it
- Hemiplegic migraine: genetics and pathophysiology.The Journal of clinical investigation · 2026Review
- Voltage-gated sodium channels in the nervous system: Molecular physiology to therapeutic interventions.Neural regeneration research · 2026Article
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- Article
- Mechanisms underlying CSD initiation implicated by genetic mouse models of migraine.The journal of headache and pain · 2025Review
- The Dawn and Advancement of the Knowledge of the Genetics of Migraine.Journal of clinical medicine · 2024Review
- Brainstem depolarization-induced lethal apnea associated with gain-of-functionProceedings of the National Academy of Sciences of the United States of America · 2024Article
- Hyperexcitable interneurons trigger cortical spreading depression in an Scn1a migraine model.The Journal of clinical investigation · 2021Article
- Sodium channelopathies of skeletal muscle and brain.Physiological reviews · 2021Review
- Headache in people with epilepsy.Nature reviews. Neurology · 2021Review
- Modeling NaV1.1/SCN1A sodium channel mutations in a microcircuit with realistic ion concentration dynamics suggests differential GABAergic mechanisms leading to hyperexcitability in epilepsy and hemiplegic migraine.PLoS computational biology · 2021Article
- DecipheringFrontiers in cellular neuroscience · 2021Article
- Voltage-Gated Sodium Channel Modulation by a New Spider Toxin Ssp1a Isolated From an Australian Theraphosid.Frontiers in pharmacology · 2021Article
- Exploring the Hereditary Nature of Migraine.Neuropsychiatric disease and treatment · 2021Review
- A Role for Vasoactive Intestinal Peptide Interneurons in Neurodevelopmental Disorders.Developmental neuroscience · 2021Review
- Bidirectional Modulation of the Voltage-Gated Sodium (Nav1.6) Channel by Rationally Designed Peptidomimetics.Molecules (Basel, Switzerland) · 2020Article
- Alternative splicing potentiates dysfunction of early-onset epileptic encephalopathy SCN2A variants.The Journal of general physiology · 2020Article
- SCN9A Epileptic Encephalopathy Mutations Display a Gain-of-function Phenotype and Distinct Sensitivity to Oxcarbazepine.Neuroscience bulletin · 2020Article
- First FHM3 mouse model shows spontaneous cortical spreading depolarizations.Annals of clinical and translational neurology · 2020Article
Corrections and comments
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Authors and funding
9 authors at 6 institutions in 6 countries.
Funding
Abstract
Familial hemiplegic migraine type 3 (FHM3) is a severe autosomal dominant migraine disorder caused by mutations in the voltage-gated sodium channel Na(V)1.1 encoded by SCN1A. We determined the functional consequences of three mutations linked to FHM3 (L263V, Q1489K, and L1649Q) in an effort to identify molecular defects that underlie this inherited migraine disorder. Only L263V and Q1489K generated quantifiable sodium currents when coexpressed in tsA201 cells with the human beta(1) and beta(2) accessory subunits. The third mutant, L1649Q, failed to generate measurable whole-cell current because of markedly reduced cell surface expression. Compared to WT-Na(V)1.1, Q1489K exhibited increased persistent current but also enhanced entry into slow inactivation as well as delayed recovery from fast and slow inactivation, thus resulting in a predominantly loss-of-function phenotype further demonstrated by a greater loss of channel availability during repetitive stimulation. In contrast, L263V exhibited gain-of-function features, including delayed entry into, as well as accelerated recovery from, fast inactivation; depolarizing shifts in the steady-state voltage dependence of fast and slow inactivation; increased persistent current; and delayed entry into slow inactivation. Notably, the two mutations (Q1489K and L1649Q) that exhibited partial or complete loss of function are linked to typical FHM, whereas the gain-of-function mutation L263V occurred in a family having both FHM and a high incidence of generalized epilepsy. We infer from these data that a complex spectrum of Na(V)1.1 defects can cause FHM3. Our results also emphasize the complex relationship between migraine and epilepsy and provide further evidence that both disorders may share common molecular mechanisms.
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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.