Abstract
Mutations in GDP-mannose pyrophosphorylase B (GMPPB) cause dystroglycanopathy, a rare neuromuscular disorder characterized by α-dystroglycan hypoglycosylation, yet the pathogenic mechanisms and therapeutic options remain poorly defined. To dissect the molecular basis of dystroglycanopathy, we generate Gmppb knockout and knock-in (P32L and R287Q) mice. We show that homozygous Gmppb knockout and P32L mutant mice (both male and female) display embryonic lethality, while heterozygous Gmppb-P32L (GmppbP32L/+) mice (both male and female) develop progressive muscular dystrophy accompanied by Purkinje cell loss, peripheral demyelination, and impaired nerve conduction. Integrated biochemical, transcriptomic, metabolomic and glycoproteomic analyses reveal widespread protein hypoglycosylation, metabolic dysregulation and suppressed Wnt/β-catenin signaling, resulting in defective differentiation and regeneration of muscle stem cells. Pharmacological activation of Wnt signaling with CHIR-99021 restores myogenic capacity and improves regeneration after injury. Furthermore, AAV-mediated GMPPB gene replacement reinstates α-dystroglycan glycosylation, normalizes GDP-mannose levels, and rescues motor and electrophysiological defects. Collectively, our findings establish GmppbP32L/+ mice as a faithful model of GMPPB-associated dystroglycanopathy and demonstrate that Wnt pathway activation and AAV-based gene therapy represent promising strategies for treating glycosylation-defective muscular dystrophies.
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Data availability
All RNA-seq data sets that were generated in this study have been deposited in the Gene Expression Omnibus, with accession number GSE268450 for cell-derived RNA-seq data and GSE268448 for RNA-seq data derived from mouse muscle tissues. Untargeted metabolomics data sets have been deposited in MetaboLights with identifier number MTBLS10214(https://www.ebi.ac.uk/metabolights/reviewer72fc43b3-6b83-429f-b844-74194e1936f5). The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium (https://proteomecentral.proteomexchange.org) via the iProX partner repository with the dataset identifier PXD073832. The mutational spectrum data used to generate Fig. 1a and crystal structure of GMPPB used to generate Fig. 2b were generated in prior studies, which are appropriately cited in this article, whenever suitable. Data for all other figures are generated in this study. Source Data are provided as a Source Data file. Source data are provided with this paper.
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Acknowledgements
This work was supported by the Startup funding of Fudan University (JIF101074 to Y.W.), the Fundamental Research Funds for the Central Universities (202261051, 202262014 to H.J.). Y.W. is supported by the Pujiang Talent Project (20PJ1400700). We thank Dr. Zhigang Zhang at Fudan University for his assistance in electron microscopy, the colleagues in Keymed Biosciences for their support and advice, Dr. Lunzhi Dai at Sichuan University for his generosity in equipment sharing. I (Y.W) would like to dedicate this work to the memory of my beloved daughter, Chelsea Zechuan Shia (Oct, 2017-Jul, 2020), who carried compound mutations in GMPPB. Chelsea’s courage and resilience throughout her life were a profound source of inspiration, prompting me to broaden my research focus beyond cancer studies to include rare diseases, areas that often receive less attention and funding. Though Chelsea did not directly participate in this study, her influence is deeply interwoven with its purpose and direction. Her presence in my life has instilled in me a greater awareness of the challenges faced by patients with rare genetic conditions and a renewed commitment to contributing to research that seeks to improve their lives. In memory of Chelsea, I dedicate this work to all those affected by rare diseases, hoping that our collective efforts in scientific research will one day alleviate their suffering and bring new hope and solutions to their conditions.
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Z.F. and Y.W. conceived and designed the study. Z.F., T.W., T.Q., Y.C., J.Y., H.Y., B.Y., B.G., W.L., S.L. and Y.W. carried out experiments and analyses. C.Z. and Z.Z. performed bioinformatic analyses. Y.L. performed pathological and electron microscopic analyses. L.S., H.J., B.C., Z.Z., X.L. and Y.W. supervised the study. H.J., B.C., X.L. and Y.W. provided funding.
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Fu, Z., Wang, T., Zhang, C. et al. Gmppb-mutant mice exhibit dystroglycanopathy symptoms that are rescued with GSK3β inhibition or AAV-mediated GMPPB gene replacement. Nat Commun (2026). https://doi.org/10.1038/s41467-026-71524-7
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DOI: https://doi.org/10.1038/s41467-026-71524-7
