Factor XII in PMM2-CDG patients: role of N-glycosylation in the secretion and function of the first element of the contact pathway

Orphanet Journal of Rare Diseases

Monika Pathak¹  Jonas Emsley¹  Mercedes Serrano²  Alberto López-Lera³  Delphine Borgel⁴  Antonia Miñano⁵  Vanessa Roldán⁵  Raquel López-Gálvez⁵  María Eugenia de la Morena-Barrio⁵  Javier Corral⁵  Vicente Vicente⁵ 

[1] Centre for Biomolecular Sciences, School of Pharmacy, University of Nottingham, NG7 2RD, Nottingham, England;Departamento de Neurología Pediátrica, Departamento de Bioquímica Clínica, Instituto de Investigación Pediátrica-Hospital Sant Joan de Déu, CIBERER U-703, Barcelona, Spain;Instituto de Investigación Sanitaria del Hospital La Paz (IdiPaz), Madrid, Spain;Centre for Biomedical Network Research On Rare Diseases (CIBERER) U-754, Hospital Universitario La Paz, Madrid, Spain;Laboratoire D’Hématologie, AP-HP, Hôpital Necker-Enfants Malades, Paris, France;UMR-S1176, Université Paris-Saclay, INSERM, 94276, Le Kremlin-Bicêtre, France;Servicio de Hematología y Oncología Médica, Hospital Universitario Morales Meseguer, Centro Regional de Hemodonación, Universidad de Murcia, IMIB-Arrixaca, CIBERER, Ronda de Garay S/N, 30003, Murcia, Spain;

关键词: Factor XII;    Congenital disorders of glycosylation;    N-glycosylation;    Angioedema;    Hemostasis;   

DOI  :  10.1186/s13023-020-01564-9

来源: Springer

【 摘 要 】

BackgroundCongenital disorders of glycosylation (CDG) are rare diseases with impaired glycosylation and multiorgan disfunction, including hemostatic and inflammatory disorders. Factor XII (FXII), the first element of the contact phase, has an emerging role in hemostasia and inflammation. FXII deficiency protects against thrombosis and the p.Thr309Lys variant is involved in hereditary angioedema through the hyperreactivity caused by the associated defective O-glycosylation. We studied FXII in CDG aiming to supply further information of the glycosylation of this molecule, and its functional and clinical effects. Plasma FXII from 46 PMM2-CDG patients was evaluated by coagulometric and by Western Blot in basal conditions, treated with N-glycosydase F or activated by silica or dextran sulfate. A recombinant FXII expression model was used to validate the secretion and glycosylation of wild-type and variants targeting the two described FXII N-glycosylation sites (p.Asn230Lys; p.Asn414Lys) as well as the p.Thr309Lys variant.ResultsPMM2-CDG patients had normal FXII levels (117%) but high proportions of a form lacking N-glycosylation at Asn414. Recombinant FXII p.Asn230Lys, and p.Asn230Lys&p.Asn414Lys had impaired secretion and increased intracellular retention compared to wild-type, p.Thr309Lys and p.Asn414Lys variants. The hypoglycosylated form of PMM2-CDG activated similarly than FXII fully glycosylated. Accordingly, no PMM2-CDG had angioedema. FXII levels did not associate to vascular events, but hypoglycosylated FXII, like hypoglycosylated transferrin, antithrombin and FXI levels did it.ConclusionsN-glycosylation at Asn230 is essential for FXII secretion. PMM2-CDG have high levels of FXII lacking N-glycosylation at Asn414, but this glycoform displays similar activation than fully glycosylated, explaining the absence of angioedema in CDG.

【 授权许可】

CC BY