Stroke-Like Episodes and Cerebellar Syndrome in Phosphomannomutase Deficiency (PMM2-CDG): Evidence for Hypoglycosylation-Driven Channelopathy

International Journal of Molecular Sciences
Mercè Izquierdo-SerraMercedes Serrano

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-o...Continue Reading

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Citations

Nov 23, 2018·Journal of Medical Genetics·Antonio Martinez-MonsenyUNKNOWN CDG Spanish Consortium
Jul 5, 2019·Journal of Thrombosis and Haemostasis : JTH·Tiffany PascreauDelphine Borgel
May 17, 2019·Journal of Inherited Metabolic Disease·Carlota PascoalPaula A Videira
Dec 1, 2019·Genes·Sandra BrasilAnd Gonçalo Valadão
May 28, 2020·Pflügers Archiv : European journal of physiology·Mercè Izquierdo-SerraMercedes Serrano
Oct 24, 2019·Orphanet Journal of Rare Diseases·Sarah C GrünertUte Spiekerkoetter
May 28, 2019·European Journal of Neurology : the Official Journal of the European Federation of Neurological Societies·G MostileM Zappia
Jan 15, 2021·Brain Sciences·Justyna PaprockaStephanie Grunewald
Dec 4, 2020·Scientific Reports·Sandra WalshJosé Manuel Fernández-Fernández
Mar 23, 2021·Frontiers in Neurology·Brahim TabarkiMajid Alfadhel
May 15, 2021·Orphanet Journal of Rare Diseases·Miriam KessiFei Yin

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Datasets Mentioned

BETA
ENSG00000140650

Methods Mentioned

BETA
glycosylation
protein assay

Software Mentioned

pClamp10
R
pClamp8

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