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

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 (Mg 2+ ) transporter. So far, patients with mutations in MAGT1 were linked to a primary immunodeficiency, characterized by chronic EBV infections attributed to a Mg 2+ 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.congenital disorders of glycosylation | CDG | XMEN | oligosaccharyltransferase complex C ongenital disorders of glycosylation (CDG) are a rapidly growing group of genetic diseases caused by defects in glycan synthesis, processing, and/or attachment. Glycosylation is an important co-and posttranslational modification of proteins and lipids, mediating their function, stability, and dynamics (1, 2). In the N-glycosylation of proteins, the lipid-linked oligosaccharide (LLO) is first built in the endoplasmic reticulum (ER) and subsequently transferred en bloc by the oligosaccharyltransferase (OST) complex from a lipidic dolichol carrier to an N-X-S/T residue of a nascent protein. Next, remodeling of the glycan structure continues in the Golgi apparatus (3). Patients with CDG show an extremely variable phenotype, ranging from intellectual disability (ID) to severe multiorgan failure and death (1).Indispensable in this meticulously orchestrated glycosylation machinery is the transfer of glycans by the OST, a multisubunit protein complex consisting of a catalytic subunit (STT3A or STT3B), six shared subunits, and complex specific accessory subunits (4). The two complexes have distinct roles: STT3A is associated with the protein translocation channel and acts in a cotranslational fashion, while sites that are missed by STT3A can be posttranslationally glycosylated by STT3B (5). This interplay ensures the full N-glycosylation of proteins in mammalian cells. Both have accessory proteins that are specific for each of the catalytic subunits: DC2 and KCP2 are indispensable for STT3A function (6), while STT3B requires either MAGT1 or TUSC3 (7, 8). These two mu...

Defective glycosylation and multisystem abnormalities characterize the primary immunodeficiency XMEN disease

“…Because of the broader scope of the clinical findings, we sought additional pathogenetic mechanisms besides the alteration of Mg 2+ transport. Our bioinformatics analysis and other data showed that MAGT1 is the human homolog of the yeast OST3/6 subunit of the OST complex and functions in NLG (15,16,19,22). The recently reported structure of the yeast OST complex showed an integral association of 2 TM helices of OST3 with TM segments of the major catalytic STT3 subunit (32) ( Figure 5A).…”

“…Our glycoproteomics analysis also revealed that defective glycosylation in XMEN disease preferentially affects NxS sequons. We found that most affected glycosites were located within 60 show that sTfs from patients with XMEN also have a mild defect in final processing of the glycans (22). Furthermore, and in contrast with most CDG type I in which Apo-CIII is not affected, patients with XMEN may also have an OLG defect in Apo-CIII, which could be secondary to defective NLG of components of the OLG enzymatic apparatus.…”

“…More recently, a different clinical phenotype manifested by intellectual and developmental disability was described for 2 patients with MAGT1 mutations. These individuals had abnormal glycosylation as determined by serum transferrin isoelectric focusing (sTf IEF) and hypoglycosylated STT3B-dependent substrates in patient-derived cell lines (22). However, the extent of the glycosylation defect and an in-depth analysis of the glycopeptides affected by loss of MAGT1 in human lymphocytes have not been described.…”

Signaling pathways involved in the T‐cell‐mediated immunity against Epstein‐Barr virus: Lessons from genetic diseases

“…In this setting, one can speculate that the defect in NKG2D N‐glycosylation (which might depend on Mg ++ ) increases NKG2D degradation by the ubiquitin‐proteasome pathway and thus leads to an impairment in NKG2D expression. This hypothesis is supported by the observation of an N ‐glycosylation defect in three recently described new patients with MAGT1 deficiency . Intriguingly, two of these patients had developmental delay but no signs of immunodeficiency ‐ possibly because they have not yet encountered EBV.…”

“…The expression of CD70 can be induced on a variety of immune cells, including dendritic cells and activated B and T cells . However, CD70 is not expressed on human peripheral blood mononuclear cells ‐ with the exception of a small subset of B cells . CD70 is also strongly expressed by B‐cell lymphomas and other cancers, such as carcinomas .…”