ArticleHuman molecular genetics2013
Missense mutation in mouse GALC mimics human gene defect and offers new insights into Krabbe disease.
Article in Human molecular genetics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 58 citations in OpenAlex.
- Schwann Cell-Specific ATG7-Dependent Autophagy Protects Myelin in a Mouse Model of Krabbe Disease.Glia · 2026Article
- Validating a Human Cell Model of Null Galactosylceramidase (GALC) Enzyme Activity That Recapitulates Krabbe Disease.Journal of inherited metabolic disease · 2026Article
- Clinical and molecular characterization of Krabbe disease in Iranian patients: case report and literature review.BMC neurology · 2026Review
- Pedigree Case Report of adult-onset phenotypically heterogeneous Krabbe disease.Frontiers in genetics · 2026Article
- Neuroimmunology in globoid cell leukodystrophy: A comprehensive review including treatments, models, and neuroimmune mechanisms underlying neuropathology.Journal of neuroimmunology · 2025Review
- Ablation of lipocalin-2 reduces neuroinflammation in a mouse model of Krabbe disease.Scientific reports · 2024Article
- Human iPSC-derived myelinating organoids and globoid cells to study Krabbe Disease.bioRxiv : the preprint server for biology · 2024Article
- Perinatal loss of galactosylceramidase in both oligodendrocytes and microglia is crucial for the pathogenesis of Krabbe disease in mice.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
- Macrophage transplantation rescues RNASET2-deficient leukodystrophy by replacing deficient microglia in a zebrafish model.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Article
- CD8+ T cell depletion prevents neuropathology in a mouse model of globoid cell leukodystrophy.The Journal of experimental medicine · 2023Article
- Article
- A zebrafish model of combined saposin deficiency identifies acid sphingomyelinase as a potential therapeutic target.Disease models & mechanisms · 2023Article
- Polymer-based drug delivery systems under investigation for enzyme replacement and other therapies of lysosomal storage disorders.Advanced drug delivery reviews · 2023Review
- Neuron-specific ablation of the Krabbe disease gene galactosylceramidase in mice results in neurodegeneration.PLoS biology · 2022Article
- Efficacy and Safety of a Krabbe Disease Gene Therapy.Human gene therapy · 2022Article
- Expression of Ripk1 and DAM genes correlates with severity and progression of Krabbe disease.Human molecular genetics · 2021Article
- Review
- Genetic defects in the sphingolipid degradation pathway and their effects on microglia in neurodegenerative disease.Cellular signalling · 2021Review
- The Role of Microglia in Inherited White-Matter Disorders and Connections to Frontotemporal Dementia.The application of clinical genetics · 2021Review
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Authors and funding
7 authors at 4 institutions in 1 country.
Funding
Abstract
Krabbe disease is a devastating pediatric leukodystrophy caused by mutations in the galactocerebrosidase (GALC) gene. A significant subset of the infantile form of the disease is due to missense mutations that result in aberrant protein production. The currently used mouse model, twitcher, has a nonsense mutation not found in Krabbe patients, although it is similar to the human 30 kb deletion in abrogating GALC expression. Here, we identify a spontaneous mutation in GALC, GALCtwi-5J, that precisely matches the E130K missense mutation in patients with infantile Krabbe disease. GALCtwi-5J homozygotes show loss of enzymatic activity despite normal levels of precursor protein, and manifest a more severe phenotype than twitcher, with half the life span. Although neuropathological hallmarks such as gliosis, globoid cells and psychosine accumulation are present throughout the nervous system, the CNS does not manifest significant demyelination. In contrast, the PNS is severely hypomyelinated and lacks large diameter axons, suggesting primary dysmyelination, rather than a demyelinating process. Our data indicate that early demise is due to mechanisms other than myelin loss and support an important role for neuroinflammation in Krabbe disease progression. Furthermore, our results argue against a causative relationship between psychosine accumulation, white matter loss and gliosis.
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