Abstract
Glycogen Storage Disease Type III (GSDIII) is a rare genetic disorder caused by mutations in the AGL gene, leading to a deficiency in the glycogen debranching enzyme. This results in the accumulation of abnormal glycogen in various tissues, causing a range of symptoms, including liver enlargement and hypoglycemia. Current animal models do not fully recapitulate the severe phenotypes observed in patients, highlighting the need for improved model systems. To the best of our knowledge, this study presents the first Caenorhabditis elegans model of GSDIII, which successfully exhibits disease-relevant traits, including glycogen accumulation. Using this model, we developed a computational approach based on high-throughput screening methods, enabling the identification of key genetic modulators. Notably, we demonstrate that glycogen accumulation can be rescued by genetic and pharmacological inhibition of CHK1, a gene involved in cell cycle regulation and DNA damage response, in a variant-specific manner. These findings suggest that targeting CHK1 may represent a promising therapeutic strategy for treating GSDIII, particularly when considering specific AGL mutations.
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Data availability
The data that support the findings of this study are available as “supplementary data 1–3” files. RNA-Seq data were deposited into the NIH Sequence Read Archive (SRA) under accession number PRJNA1378342 and are available at the following URL: https://www.ncbi.nlm.nih.gov/sra/?term=PRJNA1378342.
Code availability
The code that supports the findings of this study is available upon request.
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Acknowledgements
This study was funded by The Rare Diseases: Models & Mechanisms Network. We gratefully acknowledge Claudia Maios for the liquid culture experiments efforts and Audrey Labarre for technical and academic assistance.
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E.S., J.D., and H.D. conceived the study. H.D. and E.S. designed the experiments and analyses. C.M., H.D., and J.D. performed the experiments. H.D. and B.P. analyzed the data and generated the figures. H.D. wrote and prepared the manuscript. E.P. generated the strains. J.A.P. supervised the study. All authors have reviewed and approved the manuscript.
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Daghar, H., Pyman, B., Maios, C. et al. CHK1 inhibition rescues abnormal glycogen buildup in a Caenorhabditis elegans model for glycogen storage disease III. Commun Biol (2026). https://doi.org/10.1038/s42003-026-09535-9
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DOI: https://doi.org/10.1038/s42003-026-09535-9
