ArticleProceedings of the National Academy of Sciences of the United States of America2013
Nonfunctional NaV1.1 familial hemiplegic migraine mutant transformed into gain of function by partial rescue of folding defects.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers, 1 of them a synthesis that pooled it.
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Who cites it
54 citing papers in PubMed, 1 synthesis or guideline pooled it, 100 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
- Elicited Repetitive Daily Blindness Associated With Gain-of-FunctionNeurology. Genetics · 2026Article
- GABAergic neurons can facilitate the propagation of cortical spreading depolarization: experiments in mouse neocortical slices and a novel neural field computational model.PLoS computational biology · 2025Article
- Article
- Mechanisms underlying CSD initiation implicated by genetic mouse models of migraine.The journal of headache and pain · 2025Review
- Voltage-gated sodium channels in genetic epilepsy: up and down of excitability.Journal of neurochemistry · 2024Review
- 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
- Review
- Astrocytic Glutamate Transporters and Migraine.Neurochemical research · 2023Review
- Review
- The gain of function SCN1A disorder spectrum: novel epilepsy phenotypes and therapeutic implications.Brain : a journal of neurology · 2022Article
- Hyperexcitable interneurons trigger cortical spreading depression in an Scn1a migraine model.The Journal of clinical investigation · 2021Article
- Initiation of migraine-related cortical spreading depolarization by hyperactivity of GABAergic neurons and NaV1.1 channels.The Journal of clinical investigation · 2021Article
- Sodium channelopathies of skeletal muscle and brain.Physiological reviews · 2021Review
- Selective inhibition of gamma aminobutyric acid release from mouse hippocampal interneurone subtypes by the volatile anaesthetic isoflurane.British journal of anaesthesia · 2021Article
- Transfer ofMolecular therapy. Nucleic acids · 2021Article
- Epilepsy and Migraine Shared Genetic and Molecular Mechanisms: Focus on Therapeutic Strategies.Molecular neurobiology · 2021Review
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Familial hemiplegic migraine (FHM) is a rare subtype of migraine with aura. Mutations causing FHM type 3 have been identified in SCN1A, the gene encoding the Nav1.1 Na(+) channel, which is also a major target of epileptogenic mutations and is particularly important for the excitability of GABAergic neurons. However, functional studies of NaV1.1 FHM mutations have generated controversial results. In particular, it has been shown that the NaV1.1-L1649Q mutant is nonfunctional when expressed in a human cell line because of impaired plasma membrane expression, similarly to NaV1.1 mutants that cause severe epilepsy, but we have observed gain-of-function effects for other NaV1.1 FHM mutants. Here we show that NaV1.1-L1649Q is nonfunctional because of folding defects that are rescuable by incubation at lower temperatures or coexpression of interacting proteins, and that a partial rescue is sufficient for inducing an overall gain of function because of the modifications in gating properties. Strikingly, when expressed in neurons, the mutant was partially rescued and was a constitutive gain of function. A computational model showed that 35% rescue can be sufficient for inducing gain of function. Interestingly, previously described folding-defective epileptogenic NaV1.1 mutants show loss of function also when rescued. Our results are consistent with gain of function as the functional effect of NaV1.1 FHM mutations and hyperexcitability of GABAergic neurons as the pathomechanism of FHM type 3.
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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.