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

Izquierdo Serra, Mercè; Martínez Monseny, Antonio Federico; López, Laura; Carrillo García, Julia, 1993-; Edo, Albert; Ortigoza Escobar, Juan Darío; García, Óscar; Cancho Candela, Ramón; Carrasco Marina, Ma Llanos; Gutiérrez-Solana, Luis González; Cuadras, Daniel; Muchart, Jordi; Montero, Raquel; Artuch, Rafael; Pérez Cerdá, Celia; Pérez, Belén; Pérez Dueñas, Belén; Macaya, Alfons; Fernández-Fernández, José Manuel, 1967-; Serrano, Mercedes L.

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, Mercèca
dc.contributor.author Martínez Monseny, Antonio Federicoca
dc.contributor.author López, Lauraca
dc.contributor.author Carrillo García, Julia, 1993-ca
dc.contributor.author Edo, Albertca
dc.contributor.author Ortigoza Escobar, Juan Daríoca
dc.contributor.author García, Óscarca
dc.contributor.author Cancho Candela, Ramónca
dc.contributor.author Carrasco Marina, Ma Llanosca
dc.contributor.author Gutiérrez-Solana, Luis Gonzálezca
dc.contributor.author Cuadras, Danielca
dc.contributor.author Muchart, Jordica
dc.contributor.author Montero, Raquelca
dc.contributor.author Artuch, Rafaelca
dc.contributor.author Pérez Cerdá, Celiaca
dc.contributor.author Pérez, Belénca
dc.contributor.author Pérez Dueñas, Belénca
dc.contributor.author Macaya, Alfonsca
dc.contributor.author Fernández-Fernández, José Manuel, 1967-ca
dc.contributor.author Serrano, Mercedes L.ca
dc.date.accessioned 2018-04-20T07:17:09Z
dc.date.available 2018-04-20T07:17:09Z
dc.date.issued 2018
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.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.doi http://dx.doi.org/10.3390/ijms19020619
dc.identifier.issn 1422-0067
dc.identifier.uri http://hdl.handle.net/10230/34420
dc.language.iso eng
dc.publisher MDPIca
dc.relation.ispartof International Journal of Molecular Sciences. 2018 Feb;19(2):619
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2015-69762-R
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.accessRights info:eu-repo/semantics/openAccess
dc.rights.uri http://creativecommons.org/licenses/by/4.0/
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.title Stroke-like episodes and cerebellar syndrome in phosphomannomutase deficiency (PMM2-CDG): Evidence for hypoglycosylation-driven channelopathyca
dc.type info:eu-repo/semantics/article
dc.type.version info:eu-repo/semantics/publishedVersion

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