β4GALT1-CDG Uncovers a Novel Mechanism of von Willebrand Factor Deficiency through Impaired Glycosylation and Accelerated Clearance
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Introduction Congenital disorders of glycosylation (CDG) are rare multisystemic diseases caused by defects in protein and lipid glycosylation. β4GALT1-CDG, due to B4GALT1 mutations, impairs N-glycan galactosylation, leading to coagulopathy and thrombocytopenia. However, mechanisms underlying the bleeding phenotype remain poorly understood. Here, we report a patient with β4GALT1-CDG exhibiting a complex hemostatic disorder involving platelets and plasma factors. Notably, we identify a previously unrecognized reduction in von Willebrand factor (VWF) levels, expanding the hemostatic spectrum of CDG. Method Evaluation included coagulation, platelet function, genetic, and desmopressin tests. Platelet and plasma glycoproteins were analyzed by Western blot and lectin binding; N-glycans by mass spectrometry. MK differentiation and proplatelet formation were assessed from patient CD34+cells cultured with thrombopoietin and stem cell factor. Results The patient, born to consanguineous parents, presented with recurrent mucocutaneous bleeding, mild thrombocytopenia, and combined deficiencies in FVIII, FXI, and antithrombin. VWF antigen was persistently low (~35%) with prolonged PFA closure times. However, VWF multimer analysis and FVIII–VWF binding were normal, and no mutations were identified in the VWF gene, ruling out von Willebrand disease. Glycomic analyses revealed loss of galactose and sialic acid residues in serum, consistent with a β4GALT1-CDG. Genetic testing identified a homozygous B4GALT1 c.1013del (p.Cys338Phefs*3) variant, predicted to truncate the catalytic lid domain of β4GALT1 and abolish enzymatic function. Both plasmatic and platelet VWF and CD41, GPVI, β1-integrin, PEAR1, GPIbα platelets receptors exhibited a molecular weight shift consistent with hypogalactosylation. This alteration was nevertheless associated with enhanced aggregation and αIIbβ3 activation, reflecting a hyperreactive platelet phenotype. Importantly, analysis of MK differentiation showed normal maturation and proplatelet formation, indicating that the mild thrombocytopenia was not due to an intrinsic defect in MK development but likely secondary to peripheral mechanisms. Desmopressin testing elicited a transient rise in VWF levels followed by a rapid decline, consistent with accelerated clearance of VWF. Conclusion This case broadens the clinical and mechanistic spectrum of β4GALT1-CDG by revealing, for the first time, VWF deficiency due to glycosylation-dependent accelerated clearance. Beyond combined factor deficiencies and platelet glycoprotein alterations, these findings uncover a new regulatory layer linking β4GALT1 dysfunction to impaired plasma glycoprotein homeostasis. Preservation of megakaryopoiesis further supports dissociation between thrombocytopenia and intrinsic MK defects. Altogether, this study highlights the pivotal role of galactosylation in maintaining platelet and VWF stability, providing novel insights into glycan-dependent regulation of hemostasis in CDG. Publication History Article published online: 17 February 2026 © 2026. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- β4GALT1-CDG Uncovers a Novel Mechanism of von Willebrand Factor Deficiency through Impaired Glycosylation and Accelerated Clearance
- Date Crossref
- 01/02/2026
- Éditeur
- Georg Thieme Verlag KG
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Hôpital Necker-Enfants Malades Centre de Traitement de l'Hémophilie pays non établi dans la noticeÉtablissement de santé
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Inserm pays non établi dans la noticeOrganisme public
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Université Paris-Saclay Hôpital Bicêtre pays non établi dans la noticeUniversité ou école supérieure
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Bicêtre Hospital pays non établi dans la noticeÉtablissement de santé
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Assistance Publique – Hôpitaux de Paris pays non établi dans la noticeÉtablissement de santé
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Hôpital Bichat-Claude-Bernard Biochimie Métabolique et Cellulaire pays non établi dans la noticeÉtablissement de santé
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Commissariat à l'Énergie Atomique et aux Énergies Alternatives pays non établi dans la noticeOrganisme public
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Institut National de Recherche pour l'Agriculture pays non établi dans la noticeOrganisme public
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CEA Paris-Saclay pays non établi dans la noticeOrganisme public
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Médicaments et Technologies pour la Santé pays non établi dans la noticeStructure de recherche
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Institut Gustave Roussy pays non établi dans la noticeStructure de recherche
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Laboratoire d'hématologie générale pays non établi dans la noticeStructure de recherche
Centre de Traitement de l'Hémophilie — Hôpital Necker-Enfants Malades, Inserm et Hôpital Bicêtre — Université Paris-Saclay, avec 9 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.