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http://hdl.handle.net/2445/183491
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DC Field | Value | Language |
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dc.contributor.author | Royal, Perrine | - |
dc.contributor.author | Andres, Alba | - |
dc.contributor.author | Ávalos Prado, Pablo | - |
dc.contributor.author | Verkest, Clément | - |
dc.contributor.author | Wdziekonski, Brigitte | - |
dc.contributor.author | Schaub, Sébastien | - |
dc.contributor.author | Baron, Anne | - |
dc.contributor.author | Lesage, Florian | - |
dc.contributor.author | Gasull Casanova, Xavier | - |
dc.contributor.author | Levitz, Joshua | - |
dc.contributor.author | Sandoz, Guillaume | - |
dc.date.accessioned | 2022-02-24T16:37:25Z | - |
dc.date.available | 2022-02-24T16:37:25Z | - |
dc.date.issued | 2019-01-16 | - |
dc.identifier.issn | 0896-6273 | - |
dc.identifier.uri | http://hdl.handle.net/2445/183491 | - |
dc.description.abstract | Mutations in ion channels contribute to neurological disorders, but determining the basis of their role in pathophysiology is often unclear. In humans, 2 mutations have been found to produce a dominant negative for TRESK, a two-pore-domain K+ channel implicated in migraine: TRESK-MT, a 2 bp frameshift mutation (F139WfsX24) and TRESK-C110R, a missense mutation. Despite the fact that both mutants strongly inhibit TRESK, only TRESK-MT leads to an increase in sensory neuron excitability and is associated with a migraine phenotype. Here, we identify a new mechanism, termed frameshift mutation induced Alternative Translation Initiation (fsATI) that may explain why TRESK-MT but not TRESK-C110R is associated with migraine disorder. fsATI leads, from the same TRESK-MT mRNA, to two proteins: TRESK-MT1 and TRESK-MT2. We show that by co-assembling with and inhibiting TREK1 and TREK2, another subfamily of K2P channels, overexpression of TRESK-MT2 increases trigeminal sensory neuron excitability, a key component of migraine induction, leading to a migraine-like phenotype. This finding identifies TREK as a potential molecular target in migraine pathophysiology and resolves the contradictory lack of effect of TRESK-C110R which targets only TRESK and not TREK. Finally, taking into account the potential for fsATI allowed us to identify a new migraine-related TRESK mutant, Y121LfsX44, which also leads to the production of two TRESK fragments, indicating that this mechanism may be widespread. Together, our results suggest that genetic analysis of disease-related mutations should consider fsATI as a distinct class of mutations. | - |
dc.format.extent | 68 p. | - |
dc.format.mimetype | application/pdf | - |
dc.language.iso | eng | - |
dc.publisher | Cell Press | - |
dc.relation.isformatof | Versió postprint del document publicat a: https://doi.org/10.1016/j.neuron.2018.11.039 | - |
dc.relation.ispartof | Neuron, 2019, vol. 101, num. 1, p. 232-245 | - |
dc.relation.uri | https://doi.org/10.1016/j.neuron.2018.11.039 | - |
dc.rights | cc-by-nc-nd (c) Elsevier, 2019 | - |
dc.rights.uri | https://creativecommons.org/licenses/by-nc-nd/4.0/ | - |
dc.source | Articles publicats en revistes (Biomedicina) | - |
dc.subject.classification | Canals de potassi | - |
dc.subject.classification | Migranya | - |
dc.subject.other | Potassium channels | - |
dc.subject.other | Migraine | - |
dc.title | Migraine-Associated TRESK Mutations Increase Neuronal Excitability through Alternative Translation Initiation and Inhibition of TREK | - |
dc.type | info:eu-repo/semantics/article | - |
dc.type | info:eu-repo/semantics/acceptedVersion | - |
dc.identifier.idgrec | 686586 | - |
dc.date.updated | 2022-02-24T16:37:25Z | - |
dc.rights.accessRights | info:eu-repo/semantics/openAccess | - |
Appears in Collections: | Articles publicats en revistes (Institut de Neurociències (UBNeuro)) Articles publicats en revistes (IDIBAPS: Institut d'investigacions Biomèdiques August Pi i Sunyer) Articles publicats en revistes (Biomedicina) |
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