GMPPB‐CDG Results in Lysosomal Dysfunction and Acid Alpha‐Glucosidase Deficiency
Authors: Carla Damiano, Antonietta Tarallo, Vincenza Gragnaniello, Sandra Strollo, Simona Fecarotta, M Rosaria Tuzzi, Elena Polishchuk, Sandro Montefusco, Anna Valanzano, Antonia Assunto, Nadia Minopoli, Roberto Della Casa, Roman Polishchuk, Stijn L M in 't Groen, Diego Luis Medina, Enrico Bertini, Rosalba Carrozzo, Julia Emmerich, Benedikt Schoser, W W M Pim Pijnappel, Giancarlo Parenti
Year: 2026
Sources: Journal of Inherited Metabolic Disease
Abstract:
GDP-mannose pyrophosphorylase B (GMPPB) deficiency is a congenital disorder of glycosylation due to pathogenic variants of the GMPPB gene. GMPPB catalyzes GDP-mannose synthesis, an early step in multiple glycosylation pathways, including N-glycosylation, O-mannosylation, C-mannosylation, and glycosylphosphatidylinositol-anchor formation. In fibroblasts (N = 3), myoblasts (N = 4) and in muscle biopsies (N = 4) from a total of 7 GMPPB-deficient patients we found evidence of glycogen accumulation, both in cytosol and in lysosome-like vesicles, presence of heterogeneous storage material, and expansion of the lysosomal compartment. Due to the excess of glycogen in cells and tissues, we investigated acid alpha-glucosidase (GAA) in cultured GMPPB fibroblasts. GAA activity was reduced in GMPPB cells, with an impaired protein maturation and lysosomal localization. Incubation of cells with human recombinant GAA (rhGAA), that is fully glycosylated, showed complete correction of GAA activity, normal processing and lysosomal trafficking, with complete clearance of glycogen storage. These results suggest a secondary impairment of specific lysosomal functions in GMPPB deficiency and add information on the complexity of the pathophysiology of this disorder.
Category: journals