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dc.creatorFiore, Michele
dc.creatorEstevez Povedano, Raúl
dc.creatorGaitán Peñas, Héctor
dc.creatorEspinoza Arias, Mauricio
dc.creatorVásquez Cerdas, Melissa
dc.creatorVindas Smith, Rebeca
dc.creatorPusch, Michael
dc.creatorMorales Montero Fernando
dc.date.accessioned2022-03-30T19:20:59Z
dc.date.available2022-03-30T19:20:59Z
dc.date.issued2014
dc.identifier.citationhttps://www.cell.com/biophysj/fulltext/S0006-3495(13)02084-5#%20es_ES
dc.identifier.urihttps://hdl.handle.net/10669/86339
dc.description.abstractMutations in CLCN1 coding for the muscle ClC-1 Cl- channel lead to dominant (Thomsen's disease) of recessive (Becker's disease) myotonia. Here we characterized several CLCN1 mutations identified in Costa Rica myotonia patients: Q412P (Morales 2008. RevBiolTrop 56:1), R105C, Q154R, and F167L (R105C and F167L have been described earlier in German families (Meyer-Kleine 1995. AmJHumGenet57:1325, Zhang 2000. Neurology54:937). In different families, the Q412P mutation was found to be inherited both in recessive and dominant fashion. We studied the Cl- currents generated by these mutants in Xenopus oocytes using electrophysiological techniques, and for the Q412P mutant also surface membrane expression. Assaying for fast and common gating properties and single channel conductance, we found that none of the mutations exhibited significant alterations of gating parameters or conductance. In fact, mutations R105C, Q154R, and F167L were indistinguishable from WT ClC-1 (in agreement with earlier studies for R105C and F167L (Desaphy 2013, ExpNeurol 248:530). However, mutation Q412P displayed a dramatically reduced current density and a reduced surface expression. However, mimicking the heterozygous status of patients by co-injecting WT and mutant RNA in a 1:1 ratio did not reveal a significant reduction of current density compared to the injection of the half amount of WT. Our results indicate that Q412P does not exert a dominant negative effect on WT and that the pathophysiology of the R105C, Q154R, and F167L mutations is not due to reduced open probability or single channel current, but that these mutations must affect mechanisms that are not well reproduced in a non-skeletal muscle expression systems. The lack of dominance of Q412P might be due to early protein degradation (before being able to interact with WT subunits) or to a silent phenotype in WT/Q412P heteromers.es_ES
dc.description.sponsorshipTelethon Italy (grant GGP 12008 to M.P.), the Jepa Limmatfoundation, the Compagnia San Paolo (M.P.); SAF2012-31486, 2012 SGR719 and ICREA Academia Prize (RE)es_ES
dc.description.sponsorshipUniversidad de Costa Rica/[742-B4-318]/UCR/Costa Ricaes_ES
dc.description.sponsorshipConsejo Nacional para Investigaciones Científicas y Tecnológicas/[]/CONICIT/Costa Ricaes_ES
dc.description.sponsorshipMinisterio de Ciencia, Innovación, Tecnología y Telecomunicaciones/[]/MICITT/Costa Ricaes_ES
dc.description.sponsorshipTelethon Italia/[GGP 12008]/Italiaes_ES
dc.description.sponsorshipJepa-Limmat Foundation/[]//Italiaes_ES
dc.description.sponsorshipCompagnia di San Paolo/[]//Italiaes_ES
dc.description.sponsorshipCompagnia di San Paolo/[SAF2012-31486]//Italiaes_ES
dc.description.sponsorshipCompagnia di San Paolo/[2012 SGR719]//Italiaes_ES
dc.description.sponsorshipICREA Acadèmia Prize/[]/Españaes_ES
dc.language.isoenges_ES
dc.sourceBiophysical Journal, vol.106(2), p.147aes_ES
dc.subjectCLCN1es_ES
dc.subjectXenopuses_ES
dc.subjectMyotoniaes_ES
dc.subjectChannelopathieses_ES
dc.titleReduced current density and surface expression of a CLCN1 mutation causing dominant or recessive myotonia in Costa Ricaes_ES
dc.typecontribución de congresoes_ES
dc.identifier.doi10.1016/j.bpj.2013.11.849
dc.description.procedenceUCR::Vicerrectoría de Investigación::Unidades de Investigación::Ciencias de la Salud::Instituto de Investigaciones en Salud (INISA)es_ES
dc.description.procedenceUCR::Vicerrectoría de Docencia::Salud::Facultad de Medicinaes_ES
dc.identifier.codproyecto742-B4-318


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