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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 | 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.citation | 1422-0067 |
| dc.identifier.citation | http://dx.doi.org/10.3390/ijms19020619 |
| 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.abstract | 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 | application/pdf |
| dc.language.iso | eng |
| dc.publisher | MDPI |
| dc.relation | IJMS 2018 Feb; 19(2): 619 |
| dc.relation | info:eu-repo/grantAgreement/ES/1PE/SAF2015-69762-R |
| dc.rights | info:eu-repo/semantics/openAccess |
| 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 | http://creativecommons.org/licenses/by/4.0/ |
| dc.subject | Ataxia |
| dc.subject | Cerebellum |
| dc.subject | Congenital disorders of glycosylation |
| dc.subject | Magentic resonance Imaging (MRI) |
| dc.subject | Stroke-like |
| dc.subject | CaV2.1 voltage-gated calcium channel |
| 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.type | info:eu-repo/semantics/publishedVersion |
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