Verstoorde glycosfingolipidehomeostase: een belangrijke factor bij CDG

Congenital disorders of glycosylation (CDG) are a group of over 180 rare genetic disorders affecting the glycosylation pathway and resulting in hypoglycosylated proteins and lipids. Given that glycosylation is a fundamental process in all cells, CDG are often multi-systemic, with neurological symptoms being the most prevalent (81%). The exact pathomechanisms underlying each CDG are not fully understood, which complicates the development of suitable treatments, currently available only for a limited number of CDG. The impact of most CDG on protein glycosylation has been well characterized. In contrast, GSL analyses in CDG are quite limited, even though from a biochemical standpoint, numerous CDG subtypes should affect GSL synthesis. In this PhD project we have uncovered disrupted glycosphingolipid (GSL) homeostasis in multiple CDG affecting nucleotide sugar transport (SLC35A2-CDG), N-glycosylation (PMM2-CDG, MAN1B1-CDG), Golgi homeostasis (TMEM165-CDG, SLC39A8-CDG, ATP6AP1-CDG, ATP6AP2-CDG) and Golgi vesicular trafficking (COG1-CDG, COG4-CDG, COG5-CDG, COG6-CDG, COG7-CDG, COG8-CDG). In some CDG, this disruption manifested in the form of complex ganglioside deficiency, which we propose is likely related to the neurological involvement observed in all studied patients. In other disorders we observed globoside deficiency or accumulation of disialogangliosides GD3 and GD2, with or without additional GSL deficiency. This work emphasizes the need for further research into the field of GSLs in CDG, which has been overlooked for decades. With the availability of high performance mass spectrometers and optimized LC-MS methods, such as the one we developed, comprehensive and accurate characterization of GSL profiles across all CDG is now readily achievable. Analyzing GSLs is essential to improve our understanding of the pathomechanisms underlying these complex disorders and provides new insights into the development of novel treatment strategies and potential biomarkers.