Description du projet
Comprendre la physiopathologie des troubles de la glycosylation
Les anomalies congénitales de la glycosylation (CDG) sont caractérisées par des défauts de glycosylation des protéines et des lipides. Les phénotypes variables et les présentations cliniques des patients présentant les mêmes mutations génétiques ont poussé les chercheurs du projet OST-CDG-omics, financé par l’UE, à étudier de plus près les associations génotype-phénotype. À l’aide de technologies transcriptomiques et épigénomiques, ils analyseront l’impact de la mutation sur la fonction enzymatique et étudieront également les protéines les plus affectées par la glycosylation aberrante. Les travaux porteront principalement sur le gène MAGT1, un gène qui code pour un transporteur transmembranaire d’ions magnésium. Les résultats fourniront un aperçu fondamental des gènes impliqués dans la physiopathologie des CDG, avec des conséquences cliniques importantes.
Objectif
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.
Champ scientifique
Mots‑clés
Programme(s)
Régime de financement
MSCA-IF - Marie Skłodowska-Curie Individual Fellowships (IF)Coordinateur
3000 Leuven
Belgique