RT info:eu-repo/semantics/article
T1 Stroke-Like Episodes and Cerebellar Syndrome in Phosphomannomutase Deficiency (PMM2-CDG): Evidence for Hypoglycosylation-Driven Channelopathy
A1 Izquierdo-Serra, Mercè
A1 Martínez-Monseny, Antonio
A1 López, Laura
A1 Carrillo-García, Julia
A1 Edo, Albert
A1 Ortigoza-Escobar, Juan
A1 García, Óscar
A1 Cancho-Candela, Ramón
A1 Carrasco-Marina, M
A1 Gutiérrez-Solana, Luis
A1 Cuadras, Daniel
A1 Muchart, Jordi
A1 Montero, Raquel
A1 Artuch, Rafael
A1 Pérez-Cerdá, Celia
A1 Pérez, Belén
A1 Pérez-Dueñas, Belén
A1 Macaya, Alfons
A1 Fernández-Fernández, José
A1 Serrano, Mercedes
AB 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 areunknown. We analyze clinical variables to detect risk factors for SLE in a series of 43 PMM2-CDGpatients. We explore the hypothesis of abnormal CaV2.1 function due to aberrant N-glycosylation as apotential 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 nosigns of stroke. Comparison of characteristics between SLE positive versus negative patients’ groupshowed no differences. Acute and chronic phenotypes of patients with PMM2-CDG or CACNA1Achannelopathies show similarities. Hypoglycosylation of both CaV2.1 subunits (α1A and α2α)induced gain-of-function effects on channel gating that mirrored those reported for pathogenicCACNA1A mutations linked to FHM and ataxia. Unoccupied N-glycosylation site N283 at α1Acontributes to a gain-of-function by lessening CaV2.1 inactivation. Hypoglycosylation of the α2δsubunit also participates in the gain-of-function effect by promoting voltage-dependent openingof the CaV2.1 channel. CaV2.1 hypoglycosylation may cause ataxia and SLEs in PMM2-CDGpatients. Aberrant CaV2.1 N-glycosylation as a novel pathomechanism in PMM2-CDG opens newtherapeutic possibilities
PB MDPI
YR 2018
FD 2018
LK https://uvadoc.uva.es/handle/10324/64723
UL https://uvadoc.uva.es/handle/10324/64723
LA spa
NO International Journal of Molecular Sciences 2018. 2018 Feb 22;19(2). pii: E619
NO Producción Científica
DS UVaDOC
RD 25-nov-2024