GMPPA (GDP-mannose pyrophosphorylase A) functions as a regulatory subunit of the GMPPA-GMPPB mannose-1-phosphate guanylyltransferase complex that maintains GDP-mannose homeostasis 1. As a catalytically inactive subunit, GMPPA acts as an allosteric feedback inhibitor of GMPPB catalytic activity by binding GDP-alpha-D-mannose with high affinity and reducing GMPPB-mediated GDP-mannose synthesis 21. This regulatory mechanism is essential for controlling GDP-mannose levels, a critical metabolite for protein glycosylation and glycophosphatidylinositol anchor synthesis 1. GMPPA loss-of-function causes GMPPA-congenital disorder of glycosylation (CDG), characterized by the classic triad of alacrima, achalasia, and impaired intellectual development 3. Mechanistically, GMPPA deficiency leads to increased GDP-mannose accumulation and α-dystroglycan hyperglycosylation, causing neuromuscular dysfunction, cortical layering defects, and progressive neuronal loss 4. In cancer contexts, reduced GMPPA expression leads to elevated GDP-mannose levels that suppress homologous recombination repair by promoting BRCA2 degradation, enabling therapeutic exploitation in triple-negative breast cancer 5. Dietary mannose restriction partially ameliorates disease pathology in animal models by normalizing α-dystroglycan glycosylation and preventing muscle degeneration 4, suggesting therapeutic potential for this rare metabolic disorder.