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广东快乐十分稳赢大双:Mutations in MAGT1 lead to a glycosylation disorder with a variable phenotype
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MAGT1 is a controversial protein that has been described as an endoplasmic reticulum (ER) localized subunit of the oligosaccharyltransferase (OST) complex involved in the posttranslational transfer of glycans onto proteins, but also as a magnesium (Mg2+) transporter at the plasma membrane. So far, mutations in MAGT1 have been associated with Mg2+ defects causing an immunodeficiency. We demonstrate that MAGT1-deficient patients have a defect in glycosylation, and, in addition, we describe a different phenotype for the disorder. These results confirm the presumed role of MAGT1 as a subunit of the OST.
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.
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Author contributions: E.B., R.P., N.A.C., and R.G. designed research; E.B., F.S., and L.K. performed research; E.B., D.R., F.S., J.J., V.R., E.S., A.C., R. Sparkes, K.B., C.D., R. Schrijvers, and R.G. analyzed data; A.C. supervised diagnostic investigations; G.M. supervised research; and E.B., R.P., N.A.C., F.F., R.G., and G.M. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1817815116/-/DCSupplemental.
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