GMPPB-CDG Results in Lysosomal Dysfunction and Acid Alpha-Glucosidase Deficiency

Area of Science:

• Biochemistry
• Genetics
• Cell Biology

Background:

• GDP-mannose pyrophosphorylase B (GMPPB) deficiency is a congenital disorder of glycosylation.
• Pathogenic variants in the GMPPB gene disrupt GDP-mannose synthesis, affecting multiple glycosylation pathways.
• GMPPB is crucial for N-glycosylation, O-mannosylation, C-mannosylation, and GPI-anchor formation.

Purpose of the Study:

• To investigate the cellular and molecular consequences of GMPPB deficiency.
• To explore the relationship between GMPPB deficiency and lysosomal function, specifically acid alpha-glucosidase (GAA).
• To assess the therapeutic potential of recombinant GAA in GMPPB deficiency.

Main Methods:

• Analysis of fibroblasts, myoblasts, and muscle biopsies from GMPPB-deficient patients.
• Assessment of glycogen accumulation, lysosomal compartment size, and storage material.
• Measurement of GAA activity, protein maturation, and lysosomal localization in patient-derived cells.
• In vitro studies using human recombinant GAA (rhGAA) to treat GMPPB-deficient cells.

Main Results:

• GMPPB deficiency led to glycogen accumulation in both cytosol and lysosome-like vesicles.
• Lysosomal compartment expansion and heterogeneous storage material were observed.
• Reduced GAA activity, impaired maturation, and defective lysosomal localization of GAA were found in GMPPB-deficient cells.
• Treatment with rhGAA fully corrected GAA activity, processing, and lysosomal trafficking, leading to glycogen clearance.

Conclusions:

• GMPPB deficiency results in secondary impairment of specific lysosomal functions.
• Glycogen accumulation in GMPPB deficiency is linked to defective GAA activity and lysosomal trafficking.
• Recombinant GAA shows promise for treating the lysosomal dysfunction associated with GMPPB deficiency.