Mass spectrometry in the characterization of human genetic N-glycosylation defects

Human genetic diseases that affect N-glycosylation result from the defective synthesis of the N-linked sugar moiety (glycan) of glycoproteins. The role of glycans for proper protein folding and biological functions is illustrated in the variety and severity of clinical manifestations shared by congenital disorders of glycosylation (CDG). This family of inherited metabolic disorders includes defects in the assembly of the oligosaccharide precursor that lead to an under-occupancy of N-glycosylation sites (CDG-I), and defects of glycan remodeling (CDG-II). Mass spectrometry constitutes a key tool for characterization of CDG-I defects by mass resolution of native protein glycoforms that differ for glycosylation-site occupancy. Glycan MS analyses in CDG-II is mandatory to detect whenever possible a repertoire of structures to pinpoint candidate enzymes and genes responsible for the abnormal N-glycan synthesis. In this manuscript, we review the MS applications in the area of CDG and related disorders with a special emphasis on those techniques that have been already applied or might become functional for diagnosis, characterization, and treatment monitoring in some specific conditions.