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    Por favor, use este identificador para citar o enlazar este ítem:https://uvadoc.uva.es/handle/10324/64723

    Título
    Stroke-Like Episodes and Cerebellar Syndrome in Phosphomannomutase Deficiency (PMM2-CDG): Evidence for Hypoglycosylation-Driven Channelopathy
    Autor
    Izquierdo-Serra, Mercè
    Martínez-Monseny, Antonio
    López, Laura
    Carrillo-García, Julia
    Edo, Albert
    Ortigoza-Escobar, Juan
    Garcia, Oscar
    Cancho Candela, RamónAutoridad UVA
    Carrasco-Marina, M
    Gutiérrez-Solana, Luis
    Cuadras, Daniel
    Muchart, Jordi
    Montero, Raquel
    Artuch, Rafael
    Pérez-Cerdá, Celia
    Pérez, Belén
    Pérez-Dueñas, Belén
    Macaya, Alfons
    Fernández-Fernández, José
    Serrano, Mercedes
    Año del Documento
    2018
    Editorial
    MDPI
    Descripción
    Producción Científica
    Documento Fuente
    International Journal of Molecular Sciences 2018. 2018 Feb 22;19(2). pii: E619
    Zusammenfassung
    Stroke-like episodes (SLE) occur in phosphomannomutase deficiency (PMM2-CDG), and may complicate the course of channelopathies related to Familial Hemiplegic Migraine (FHM) caused by mutations in CACNA1A (encoding CaV2.1 channel). The underlying pathomechanisms are unknown. We analyze clinical variables to detect risk factors for SLE in a series of 43 PMM2-CDG patients. We explore the hypothesis of abnormal CaV2.1 function due to aberrant N-glycosylation as a potential novel pathomechanism of SLE and ataxia in PMM2-CDG by using whole-cell patch-clamp, N-glycosylation blockade and mutagenesis. Nine SLE were identified. Neuroimages showed no signs of stroke. Comparison of characteristics between SLE positive versus negative patients’ group showed no differences. Acute and chronic phenotypes of patients with PMM2-CDG or CACNA1A channelopathies show similarities. Hypoglycosylation of both CaV2.1 subunits (α1A and α2α) induced gain-of-function effects on channel gating that mirrored those reported for pathogenic CACNA1A mutations linked to FHM and ataxia. Unoccupied N-glycosylation site N283 at α1A contributes to a gain-of-function by lessening CaV2.1 inactivation. Hypoglycosylation of the α2δ subunit also participates in the gain-of-function effect by promoting voltage-dependent opening of the CaV2.1 channel. CaV2.1 hypoglycosylation may cause ataxia and SLEs in PMM2-CDG patients. Aberrant CaV2.1 N-glycosylation as a novel pathomechanism in PMM2-CDG opens new therapeutic possibilities
    Revisión por pares
    SI
    DOI
    10.3390/ijms19020619
    Patrocinador
    This work was supported by national grant PI14/00021 and PI17/00101 from the National Plan on I+D+I, cofinanced by ISC-III (Subdirección General de Evaluación y Fomento de la Investigación Sanitaria), the Spanish Ministry of Economy and Competitiveness (Grants IPT-2012-0561-010000, SAF2015-69762-R, MDM-2014-0370 through the “María de Maeztu” Programme for Units of Excellence in R&D to “Departament de Ciències Experimentals i de la Salut”), FEDER (Fondo Europeo de Desarrollo Regional), and the Migraine Research Foundation (New York, USA). Mercè Izquierdo-Serra holds a “Juan de la Cierva-Formación” Fellowship funded by the Spanish Ministry of Economy and Competitiveness
    Idioma
    spa
    URI
    https://uvadoc.uva.es/handle/10324/64723
    Tipo de versión
    info:eu-repo/semantics/publishedVersion
    Derechos
    openAccess
    Aparece en las colecciones
    • DEP55 - Artículos de revista [208]
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    2018 stroke like CDG.pdf
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