2026-04-27T12:55:17Zhttps://uvadoc.uva.es/oai/request

oai:uvadoc.uva.es:10324/647232025-02-28T13:03:42Zcom_10324_1181com_10324_931com_10324_894col_10324_1387

Izquierdo-Serra, Mercè Martínez-Monseny, Antonio López, Laura Carrillo-García, Julia Edo, Albert Ortigoza-Escobar, Juan Garcia, Oscar Cancho Candela, Ramón 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 2024-01-18T09:28:01Z 2024-01-18T09:28:01Z 2018 International Journal of Molecular Sciences 2018. 2018 Feb 22;19(2). pii: E619 https://uvadoc.uva.es/handle/10324/64723 10.3390/ijms19020619 619 2 International Journal of Molecular Sciences 19 1422-0067 Producción Científica 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 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 application/pdf spa MDPI info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by-nc-nd/4.0/ Attribution-NonCommercial-NoDerivatives 4.0 Internacional Stroke-Like Episodes and Cerebellar Syndrome in Phosphomannomutase Deficiency (PMM2-CDG): Evidence for Hypoglycosylation-Driven Channelopathy info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion SI