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...
The molecular basis of interindividual clinical variability upon infection with Staphylococcus aureus is unclear. We describe patients with haploinsufficiency for the linear deubiquitinase OTULIN, encoded by a gene on chromosome 5p. Patients present episodes of life-threatening necrosis, typically triggered by S. aureus infection. The disorder is phenocopied in patients with the 5p- (Cri-du-Chat) chromosomal deletion syndrome. OTULIN haploinsufficiency causes an accumulation of linear ubiquitin in dermal fibroblasts, but TNF-receptor NF-κB-signaling remains intact. Blood leukocyte subsets are unaffected. The OTULIN-dependent accumulation of caveolin-1 in dermal fibroblasts—but not leukocytes—facilitates the cytotoxic damage inflicted by the staphylococcal virulence factor α-toxin. Naturally elicited antibodies against α-toxin contribute to incomplete clinical penetrance. Human OTULIN haploinsufficiency underlies life-threatening staphylococcal disease by disrupting cell-intrinsic immunity to α-toxin in non-leukocytic cells.
Recently, a novel disorder coined VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome was identified in patients with adult-onset inflammatory syndromes, often accompanied by myelodysplastic syndrome1. All patients had myeloid lineage-restricted somatic mutations in UBA1 affecting the Met41 residue of the protein and resulting in decreased cellular ubiquitylation activity and hyperinflammation. We here describe the clinical disease course of two VEXAS syndrome patients with somatic UBA1 mutations of which one with a mild phenotype characterized by recurrent rash and symmetric polyarthritis, and another who was initially diagnosed with idiopathic multicentric Castleman disease and developed macrophage activation syndrome as a complication of the VEXAS syndrome. The latter patients was treated with anti-IL6 therapy (siltuximab) leading to a resolution of systemic symptoms and reduction of transfusion requirements.
STING-associated vasculopathy with onset in infancy (SAVI) is an autosomal dominant disorder due to gain-of-function mutations in STING1 , also known as TMEM173 , encoding for STING. It was reported as a vasculopathy of infancy. However, since its description a wider spectrum of associated manifestations and disease-onset has been observed. We report a kindred with a heterozygous STING mutation (p.V155M) in which the 19-year-old proband suffered from isolated adult-onset ANCA-associated vasculitis. His father suffered from childhood-onset pulmonary fibrosis and renal failure attributed to ANCA-associated vasculitis, and died at the age of 30 years due to respiratory failure. In addition, an overview of the phenotypic spectrum of SAVI is provided highlighting (a) a high phenotypic variability with in some cases isolated manifestations, (b) the potential of adult-onset disease, and (c) a novel manifestation with ANCA-associated vasculitis.
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