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Stroke-like episodes and cerebellar syndrome in phosphomannomutase deficiency (PMM2-CDG): Evidence for hypoglycosylation-driven channelopathy

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dc.contributor.author Izquierdo Serra, Mercè
dc.contributor.author Martínez Monseny, Antonio Federico
dc.contributor.author López, Laura
dc.contributor.author Carrillo García, Julia
dc.contributor.author Edo, Albert
dc.contributor.author Ortigoza Escobar, Juan Darío
dc.contributor.author García, Óscar
dc.contributor.author Cancho Candela, Ramón
dc.contributor.author Carrasco Marina, Ma Llanos
dc.contributor.author Gutiérrez-Solana, Luis González
dc.contributor.author Cuadras, Daniel
dc.contributor.author Muchart, Jordi
dc.contributor.author Montero, Raquel
dc.contributor.author Artuch, Rafael
dc.contributor.author Pérez Cerdá, Celia
dc.contributor.author Pérez, Belén
dc.contributor.author Pérez Dueñas, Belén
dc.contributor.author Macaya, Alfons
dc.contributor.author Fernández-Fernández, José Manuel, 1967-
dc.contributor.author Serrano, Mercedes L.
dc.date.accessioned 2018-04-20T07:17:09Z
dc.date.available 2018-04-20T07:17:09Z
dc.date.issued 2018
dc.identifier.citation Izquierdo-Serra M, Martínez-Monseny A, López L, Carrillo-García J, Edo A, Ortigoza-Escobar J et al. Stroke-Like Episodes and Cerebellar Syndrome in Phosphomannomutase Deficiency (PMM2-CDG): Evidence for Hypoglycosylation-Driven Channelopathy. IJMS. 2018 Feb;19(2):619. DOI: 10.3390/ijms19020619
dc.identifier.issn 1422-0067
dc.identifier.uri http://hdl.handle.net/10230/34420
dc.description.abstract 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.
dc.description.sponsorship 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.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher MDPI
dc.relation.ispartof International Journal of Molecular Sciences. 2018 Feb;19(2):619
dc.rights © 2018 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
dc.title Stroke-like episodes and cerebellar syndrome in phosphomannomutase deficiency (PMM2-CDG): Evidence for hypoglycosylation-driven channelopathy
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.3390/ijms19020619
dc.subject.keyword Ataxia
dc.subject.keyword Cerebellum
dc.subject.keyword Congenital disorders of glycosylation
dc.subject.keyword Magentic resonance Imaging (MRI)
dc.subject.keyword Stroke-like
dc.subject.keyword CaV2.1 voltage-gated calcium channel
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2015-69762-R
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion

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