Journal article
Systematic genetic, biochemical, and lipidomic characterization of GSD III fibroblast models reveals mis-annotation and defines a conserved disease lipid signature
Molecular genetics and metabolism, Vol.149(1-2), 110249
09/2026
DOI: 10.1016/j.ymgme.2026.110249
PMID: 42679456
Abstract
Glycogen storage disease type III (GSD III) is an autosomal recessive disorder caused by pathogenic variants in AGL, which encodes the glycogen debranching enzyme (GDE). Loss of GDE function impairs glycogen degradation, leading to accumulation of abnormal glycogen in liver and skeletal muscle. Clinical manifestations arise in early childhood and include hypoglycemia, hepatomegaly, and progressive myopathy. Despite significant morbidity, no disease-modifying therapies exist, due in part to a lack of rigorously validated cellular models. Patient-derived fibroblasts provide an accessible and scalable system that preserves each patient's endogenous AGL genotype and broader genetic background, enabling investigation of disease heterogeneity, genotype–phenotype relationships, and potential genetic modifiers. We performed whole-genome sequencing and phenotypic characterization of nine fibroblast lines originating from patients who were diagnosed with GSD III. Eight lines harbored biallelic pathogenic or likely pathogenic AGL variants, while one was reclassified based on absence of AGL variants and the presence of a pathogenic variant in an alternative metabolic gene. Validated GSD III fibroblasts exhibited consistent disease features, including absence of GDE protein, impaired glycogen utilization, and distinct lipidomic signatures. We generated an isogenic immortalized AGL-deficient fibroblast model which recapitulated these phenotypes. Together, these patient-derived and isogenic models provide a robust, genomically defined platform for studying the pathogenesis and phenotypic heterogenity of GSD III. Refined characterization and accessibility of these models will be useful to evaluate candidate GSD III therapeutics.
•Genomic validation identified a misclassified fibroblast line among those designated as GSD III.•Eight fibroblast lines were confirmed to harbor biallelic pathogenic AGL variants.•An isogenic immortalized AGL-deficient fibroblast model was generated and validated.•Lipidomic profiling reveals a consistent metabolic signature across GSD III models.
Details
- Title: Subtitle
- Systematic genetic, biochemical, and lipidomic characterization of GSD III fibroblast models reveals mis-annotation and defines a conserved disease lipid signature
- Creators
- K.A. Becker - University of IowaC.K. Pathmasiri - University of Illinois ChicagoE.S. Phillippi - University of Iowa, Stead Family Department of PediatricsK. Casazza - ABS Consulting (United States)D.W. Todd - University of IowaD.A. Weinstein - University of IowaK.L. Ode - University of Iowa, Stead Family Department of PediatricsA.R. Calhoun - University of Iowa, Stead Family Department of PediatricsS.M. Cologna - University of Illinois ChicagoM.L. Schultz - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Molecular genetics and metabolism, Vol.149(1-2), 110249
- DOI
- 10.1016/j.ymgme.2026.110249
- PMID
- 42679456
- NLM abbreviation
- Mol Genet Metab
- ISSN
- 1096-7192
- eISSN
- 1096-7206
- Publisher
- Elsevier Inc; SAN DIEGO
- Grant note
- College of Science at the University of Notre Dame through the Reisenauer Endowment for GSD and Related Disease Research National Cancer Institute of the National Institutes of Health: P30CA046592
This work was funded by the College of Science at the University of Notre Dame through the Reisenauer Endowment for GSD and Related Disease Research (to MLS and SMC) . The authors would also like to acknowledge use of the University of Iowa Central Microscopy Research Facility, a core resource supported by the University of Iowa Vice President for Research, and the Carver College of Medicine Department of Pediatrics start-up funds. Liver tissues were supplied by the Rogel Cancer Cener Tissue and Molecular Pathology Shared Resource Tissue Procurement Service at University of Michigan Health which is ported by the National Cancer Institute of the National Institutes of Health under award number P30CA046592. The authors would like to thank the Reisenauer family for their support.
- Language
- English
- Date published
- 09/2026
- Academic Unit
- Endocrinology and Diabetes; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Medical Genetics and Genomics
- Record Identifier
- 9985222847202771
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