MAGT1 deficiency: Novel insights into a controversial protein with a key role in N-glycosylation

Abstract

Congenital Disorders of Glycosylation (CDG) are a rapidly growing and heterogeneous group of rare metabolic diseases caused by inborn defects in glycosylation. The latter is an important posttranslational modification process of proteins and lipids. Over 50% of the proteome is glycosylated and the sugar moieties (or glycans) are essential for mediating a protein's function and stability. N-glycosylation of proteins is the major form of glycosylation and is characterized by the addition of glycan chains on the asparagine (Asn, N) residue of nascent proteins by the oligosaccharyltransferase (OST) complex. Patients with CDG show a very variable phenotype, with severe developmental delay and multi-organ failure, accompanied by neurologic symptoms and dysmorphic features. The lab recently identified candidate genes through either targeted-NGS (Next Generation Sequencing) or WES (Whole Exome Sequencing), for which the pathogenicity of the identified variants needs to be confirmed. One of those candidates is the X-linked gene MAGT1. Over the years MAGT1 has been swayed back and forth between a role as a subunit of the OST complex in the endoplasmic reticulum or as a plasma membrane localised Mg2+ transporter. We hypothesize that MAGT1 is part of the OST-complex and that one of the substrates could be an Mg2+ transporter. Assays to interrogate the (hypo)glycosylation of target proteins, the localisation of the protein, the pathogenicity of the mutations and to quantify the Mg2+ levels, etc. will be performed. Second, Whole Genome Sequencing (WGS) will be used to solve our 'unsolvable' cases, which allows us to explore the full mutational spectrum of the patients. In total 20 patients of our 'unsolvable' cohort were selected for further analysis. These patients represent clinical phenotypes that were not previously described in CDG and/or are from nuclear families with multiple affected siblings. Although they were exhaustively tested using enzymatic studies and NGS (WES or a targeted panel), no enzymatic alterations nor candidate mutations were found. With this approach, the ambition is to find new CDG genes or new types of mutations, so far never associated with CDG.status: publishe