Genetically Engineered Mouse Models Unveil Mechanisms and Therapeutic Strategies for GMPPB-Associated Dystroglycanopathy I

Recent studies have highlighted a significant association between mutations in GDP-mannose pyrophosphorylase B (GMPPB) gene with dystroglycanopathy (DGP), a rare disease characterized by neuromuscular phenotypes. To interrogate the molecular mechanisms driving the onset and progression and to identify potential therapeutic approaches for GMPPB-associated DGP, we here constructed genetically engineered mice models of Gmppb. We show that Gmppb knockout and P32L mutant mice are lethal in the homozygous form, whereas homologous R287Q mutants are viable. Heterozygous Gmppb-P32L mutant mice exhibit reduced muscle strength, decreased locomotor ability, elevated creatine kinase levels and increased centrally nucleated myofibers. Furthermore, loss of GMPPB results in defective differentiation of muscle stem cells, leading to failure to develop into mature myotubes and diminished muscle regeneration capability. Biochemical and transcriptomic analyses indicate that loss of GMPPB is associated with significant alterations in O-linked glycosylation level, intracellular Ca2+ storage and release and the Wnt/β-catenin signaling pathway. Pharmacological activation of the Wnt pathway alleviated disruption of muscle differentiation and regeneration post muscle injury in Gmppb-deficient models. Additionally, adeno-associated virus (AAV)-mediated gene replacement therapy successfully ameliorated the muscular phenotypes. Collectively, our findings provide direct evidence that impaired muscle stem cell differentiation contributes to GMPPB-associated dystroglycanopathy. Wnt pathway agonists and AAV gene therapy represent potential effective intervention strategies for treating DGP disease.