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Pàgina inicial > Articles > Articles publicats > Stroke-Like Episodes and Cerebellar Syndrome in Phosphomannomutase Deficiency (PMM2-CDG) : |
Data: | 2018 |
Resum: | 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. |
Ajuts: | Ministerio de Economía y Competitividad PI14/00021 Instituto de Salud Carlos III PI17/00101 Ministerio de Economía y Competitividad IPT-2012-0561-010000 Ministerio de Economía y Competitividad SAF2015-69762-R Ministerio de Economía y Competitividad MDM-2014-0370 |
Drets: | 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. |
Llengua: | Anglès |
Document: | Article ; recerca ; Versió publicada |
Matèria: | Ataxia ; Cerebellum ; Congenital disorders of glycosylation ; Magentic resonance Imaging (MRI) ; Stroke-like ; Ca2.1 voltage-gated calcium channel |
Publicat a: | International journal of molecular sciences, Vol. 19 (february 2018) , ISSN 1422-0067 |
21 p, 2.5 MB |