Royal, PerrineAndres, AlbaÁvalos Prado, PabloVerkest, ClémentWdziekonski, BrigitteSchaub, SébastienBaron, AnneLesage, FlorianGasull Casanova, XavierLevitz, JoshuaSandoz, Guillaume2022-02-242022-02-242019-01-160896-6273https://hdl.handle.net/2445/183491Mutations 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.68 p.application/pdfengcc-by-nc-nd (c) Elsevier, 2019https://creativecommons.org/licenses/by-nc-nd/4.0/Canals de potassiMigranyaPotassium channelsMigraineinfo:eu-repo/semantics/article6865862022-02-24info:eu-repo/semantics/openAccess