2. Academic Validation
  3. Mutations in MAGT1 lead to a glycosylation disorder with a variable phenotype

Mutations in MAGT1 lead to a glycosylation disorder with a variable phenotype

  • Proc Natl Acad Sci U S A. 2019 May 14;116(20):9865-9870. doi: 10.1073/pnas.1817815116.
Eline Blommaert 1,  Romain Péanne 1,  Natalia A Cherepanova 2,  Daisy Rymen 3,  Frederik Staels 4,  Jaak Jaeken 5,  Valérie Race 1,  Liesbeth Keldermans 1,  Erika Souche 1,  Anniek Corveleyn 1,  Rebecca Sparkes 6,  Kaustuv Bhattacharya 7,  Christine Devalck 8,  Rik Schrijvers 4,  François Foulquier 9,  Reid Gilmore 2,  Gert Matthijs 10
Affiliations

Affiliations

  • 1 Laboratory for Molecular Diagnosis, Center for Human Genetics, KU Leuven, 3000 Leuven, Belgium.
  • 2 Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01655.
  • 3 Division of Metabolic Diseases, University Children's Hospital, 8032 Zürich, Switzerland.
  • 4 KU Leuven Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, KU Leuven, 3000 Leuven, Belgium.
  • 5 Department of Pediatrics, Center for Metabolic Diseases, KU Leuven, 3000 Leuven, Belgium.
  • 6 Alberta Children's Hospital, Calgary, AB T3B 6A8, Canada.
  • 7 Genetic Metabolic Disorders Service, Children's Hospital Westmead Clinical School, University of Sydney, NSW 2145 Westmead, Australia.
  • 8 Department of Hemato-Oncology, Hôpital Universitaire Des Enfants Reine Fabiola, Université Libre de Bruxelles, 1020 Brussels, Belgium.
  • 9 Unité de Glycobiologie Structurale et Fonctionnelle, University Lille, CNRS, UMR 8576, F-59000 Lille, France.
  • 10 Laboratory for Molecular Diagnosis, Center for Human Genetics, KU Leuven, 3000 Leuven, Belgium; [email protected].
PMID: 31036665 DOI: 10.1073/pnas.1817815116
Abstract

Congenital disorders of glycosylation (CDG) are a group of rare metabolic diseases, due to impaired protein and lipid glycosylation. We identified two patients with defective serum transferrin glycosylation and mutations in the MAGT1 gene. These patients present with a phenotype that is mainly characterized by intellectual and developmental disability. MAGT1 has been described to be a subunit of the oligosaccharyltransferase (OST) complex and more specifically of the STT3B complex. However, it was also claimed that MAGT1 is a magnesium (Mg2+) transporter. So far, patients with mutations in MAGT1 were linked to a primary immunodeficiency, characterized by chronic EBV infections attributed to a Mg2+ homeostasis defect (XMEN). We compared the clinical and cellular phenotype of our two patients to that of an XMEN patient that we recently identified. All three patients have an N-glycosylation defect, as was shown by the study of different substrates, such as GLUT1 and SHBG, demonstrating that the posttranslational glycosylation carried out by the STT3B complex is dysfunctional in all three patients. Moreover, MAGT1 deficiency is associated with an enhanced expression of TUSC3, the homolog protein of MAGT1, pointing toward a compensatory mechanism. Hence, we delineate MAGT1-CDG as a disorder associated with two different clinical phenotypes caused by defects in glycosylation.

Keywords

CDG; XMEN; congenital disorders of glycosylation; oligosaccharyltransferase complex.

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