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

Daniel Cuadras, Mercedes Serrano, José M Fernández-Fernández, Alfons Macaya, Belén Pérez-Dueñas, Belén Pérez, Celia Pérez-Cerdá, Rafael Artuch, Raquel Montero, Jordi Muchart, Mercè Izquierdo-Serra, Luis G Gutiérrez-Solana, M Llanos Carrasco-Marina, Ramón Cancho-Candela, Óscar García, Juan Darío Ortigoza-Escobar, Albert Edo, Julia Carrillo-García, Laura López, Antonio F Martínez-Monseny

Journal: International journal of molecular sciences 2018;19(2):619

PMID: 29470411

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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 (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 -glycosylation as a potential novel pathomechanism of SLE and ataxia in PMM2-CDG by using whole-cell patch-clamp, -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 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 mutations linked to FHM and ataxia. Unoccupied -glycosylation site N283 at α contributes to a gain-of-function by lessening Ca2.1 inactivation. Hypoglycosylation of the α₂δ 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 -glycosylation as a novel pathomechanism in PMM2-CDG opens new therapeutic possibilities.

Address: Laboratori de Fisiologia Molecular, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08003 Barcelona, Spain. [email protected].; Genetic Medicine and Rare Diseases Pediatric Institute, Hospital Sant Joan de Déu, 08002 Barcelona, Spain. [email protected].; Unit of Child Neurology, Department of Pediatrics, Hospital Infantil Universitario Niño Jesús de Madrid, 28009 Madrid, Spain. [email protected].; Laboratori de Fisiologia Molecular, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08003 Barcelona, Spain. [email protected].; Laboratori de Fisiologia Molecular, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08003 Barcelona, Spain. [email protected].; Neuropediatric, Radiology and Clinical Biochemistry Departments, Hospital Sant Joan de Déu, 08002 Barcelona, Spain. [email protected].; U-703 Centre for Biomedical Research on Rare Diseases (CIBER-ER), Instituto de Salud Carlos III, 08002 Barcelona, Spain. [email protected].; Pediatric Department, Hospital Virgen de la Salud, 45004 Toledo, Spain. [email protected].; Pediatric Neurology Unit, Pediatrics Department, Hospital Universitario Rio Hortega, 47012 Valladolid, Spain. [email protected].; Neuropediatric Department, Pediatric Service, Hospital Universitario Severo Ochoa, Leganés, 28009 Madrid, Spain. [email protected].; Unit of Child Neurology, Department of Pediatrics, Hospital Infantil Universitario Niño Jesús de Madrid, 28009 Madrid, Spain. [email protected].; Statistics Department, Fundació Sant Joan de Déu, 08002 Barcelona, Spain. [email protected].; Neuropediatric, Radiology and Clinical Biochemistry Departments, Hospital Sant Joan de Déu, 08002 Barcelona, Spain. [email protected].; U-703 Centre for Biomedical Research on Rare Diseases (CIBER-ER), Instituto de Salud Carlos III, 08002 Barcelona, Spain. [email protected].; Neuropediatric, Radiology and Clinical Biochemistry Departments, Hospital Sant Joan de Déu, 08002 Barcelona, Spain. [email protected].; U-703 Centre for Biomedical Research on Rare Diseases (CIBER-ER), Instituto de Salud Carlos III, 08002 Barcelona, Spain. [email protected].; Neuropediatric, Radiology and Clinical Biochemistry Departments, Hospital Sant Joan de Déu, 08002 Barcelona, Spain. [email protected].; U-703 Centre for Biomedical Research on Rare Diseases (CIBER-ER), Instituto de Salud Carlos III, 08002 Barcelona, Spain. [email protected].; Centro de Diagnóstico de Enfermedades Moleculares (CEDEM), Universidad Autónoma de Madrid (UAM), U-746 Centre for Biomedical Research on Rare Diseases (CIBER-ER) Madrid, Instituto de Salud Carlos III, IdiPAZ, 28009 Madrid, Spain. [email protected].; Centro de Diagnóstico de Enfermedades Moleculares (CEDEM), Universidad Autónoma de Madrid (UAM), U-746 Centre for Biomedical Research on Rare Diseases (CIBER-ER) Madrid, Instituto de Salud Carlos III, IdiPAZ, 28009 Madrid, Spain. [email protected].; Neuropediatric, Radiology and Clinical Biochemistry Departments, Hospital Sant Joan de Déu, 08002 Barcelona, Spain. [email protected].; U-703 Centre for Biomedical Research on Rare Diseases (CIBER-ER), Instituto de Salud Carlos III, 08002 Barcelona, Spain. [email protected].; Grup de Recerca en Neurologia Pediàtrica, Institut de Recerca Vall d'Hebron, Universitat Autònoma de Barcelona, Secció de Neurologia Pediàtrica, Hospital Universitari Vall d'Hebron, 08002 Barcelona, Spain. [email protected].; Laboratori de Fisiologia Molecular, Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08003 Barcelona, Spain. [email protected].; Genetic Medicine and Rare Diseases Pediatric Institute, Hospital Sant Joan de Déu, 08002 Barcelona, Spain. [email protected].; Neuropediatric, Radiology and Clinical Biochemistry Departments, Hospital Sant Joan de Déu, 08002 Barcelona, Spain. [email protected].; U-703 Centre for Biomedical Research on Rare Diseases (CIBER-ER), Instituto de Salud Carlos III, 08002 Barcelona, Spain. [email protected].

DOI: 10.3390/ijms19020619

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MeSH Terms: Adolescent, Amino Acid Sequence, Calcium Channels, Cerebellar Diseases, Channelopathies, Child, Child, Preschool, Electroencephalography, Female, Glycosylation, HEK293 Cells, Humans, Ion Channel Gating, Magnetic Resonance Imaging, Male, Mutation, Phosphotransferases (Phosphomutases), Stroke, Tunicamycin