Untangling the pathophysiology of congenital disorders of glycosylation affecting the OST complex: OST-CDG-omics

Programme(s): H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility

Topic(s): MSCA-IF-2019 - Individual Fellowships

Call for proposal: H2020-MSCA-IF-2019

Funding Scheme: MSCA-IF-EF-ST - Standard EF

Grant agreement ID: 894669

Project description:

Insight into the pathophysiology of glycosylation disorders

Congenital disorders of glycosylation (CDG) are characterised by defects in the glycosylation of proteins and lipids. The variable phenotypes and clinical presentations of patients with the same genetic mutations have urged scientists of the EU-funded OST-CDG-omics project to study genotype–phenotype associations more closely. Using transcriptomics and epigenomics technologies, they will analyse the impact of mutation on enzyme function and also study the proteins most affected by aberrant glycosylation. The work will mainly focus on the MAGT1 gene, a gene that codes for a transmembrane transporter of magnesium ions. Results will offer fundamental insight into the genes implicated in the pathophysiology of CDG, with important clinical consequences.

Objective:

Congenital disorders of glycosylation (CDG) are a group of over 100 inherited disorders characterised by defective glycosylation of proteins and lipids. Although the phenotypic and genetic characteristics of CDG as a whole are well established, their pathophysiology is poorly understood. In addition, the phenotype of affected patients is extremely variable, with dramatically different clinical presentations often appearing in patients with mutations in the same gene. I plan to investigate the link between pathogenic mutation and phenotype using recent advances in omics technologies, with a focus on the regulation of genes implicated in the pathophysiology of CDG.

Firstly, using transcriptomics and epigenomics, I will identify the mechanism by which mutations in homologous genes encoding subunits of the oligosaccharyltransferase (OST) complex cause divergent phenotypes, thought to be due to differences in the regulation of tissue-specific transcription. The primary model for these studies will be the MAGT1 gene, mutations in which can lead to either a severe developmental disorder (MAGT1-CDG) or an isolated primary immune deficiency (XMEN). Secondly, using glycoproteomic techniques, I will study the proteins most affected by aberrant glycosylation in CDG affecting the OST, thereby characterising their pathophysiology in both patient-derived and modified cell lines. findings will be further investigated using targeted techniques such as LC-MS/MS. In summary, this study will simultaneously provide valuable insight into both the pathophysiology of CDG and the functional regulation of the OST complex, an understudied aspect of cell biology.