2026-04-14T09:26:10Zhttps://recercat.cat/oai/request
oai:recercat.cat:2072/4595502026-03-13T08:05:39Zcom_2072_98col_2072_378192
RECERCAT author Izquierdo-Serra, Mercè author Martínez-Monseny, Antonio F. author López López, Laura author Carrillo-García, Julia author Edo Salvador, Ángel author Ortigoza-Escobar, Juan Darío author García Campos, Óscar author Cancho-Candela, Ramón author Carrasco-Marina, M. Llanos author González Gutiérrez-Solana, Luis author Cuadras, Daniel author Muchart, Jordi author Montero, Raquel author Artuch, R. author Pérez-Cerdá, Celia author Pérez, Belén author Pérez-Dueñas, Belén author Macaya Ruiz, Alfons author Fernández-Fernández, José Manuel author Serrano, Mercedes author Universitat Autònoma de Barcelona 2018 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 Ca2.1 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 Ca2.1 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 Ca2.1 subunits (α and α) 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 α contributes to a gain-of-function by lessening Ca2.1 inactivation. Hypoglycosylation of the αδ subunit also participates in the gain-of-function effect by promoting voltage-dependent opening of the Ca2.1 channel. Ca2.1 hypoglycosylation may cause ataxia and SLEs in PMM2-CDG patients. Aberrant Ca2.1 N -glycosylation as a novel pathomechanism in PMM2-CDG opens new therapeutic possibilities. open access Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. https://creativecommons.org/licenses/by/4.0/ Ataxia Cerebellum Congenital disorders of glycosylation Magentic resonance Imaging (MRI) Stroke-like Ca2.1 voltage-gated calcium channel Stroke-Like Episodes and Cerebellar Syndrome in Phosphomannomutase Deficiency (PMM2-CDG) : Evidence for Hypoglycosylation-Driven Channelopathy Article