The Pex1-G844D mouse: a model for mild human Zellweger spectrum disorder
Open accessAbstract
Zellweger spectrum disorder (ZSD) is a disease continuum that results from inherited defects in PEX genes essential for normal peroxisome assembly. These autosomal recessive disorders impact brain development and also cause postnatal liver, adrenal, and kidney dysfunction, as well as loss of vision and hearing. The hypomorphic PEX1-G843D missense allele, observed in approximately 30% of ZSD patients, is associated with milder clinical and biochemical phenotypes, with some homozygous individuals surviving into early adulthood. Nonetheless, affected children with the PEX1-G843D allele have intellectual disability, failure to thrive, and significant sensory deficits. To enhance our ability to test candidate therapies that improve human PEX1-G843D function, we created the novel Pex1-G844D knock-in mouse model that represents the murine equivalent of the common human mutation. We show that Pex1-G844D homozygous mice recapitulate many classic features of mild ZSD cases, including growth retardation and fatty livers with cholestasis. In addition, electrophysiology, histology, and gene expression studies provide evidence that these animals develop a retinopathy similar to that observed in human patients, with evidence of cone photoreceptor cell death. Similar to skin fibroblasts obtained from ZSD patients with a PEX1-G843D allele, we demonstrate that murine cells homozygous for the Pex1-G844D allele respond to chaperone-like compounds, which normalizes peroxisomal β-oxidation. Thus, the Pex1-G844D mouse provides a powerful model system for testing candidate therapies that address the most common genetic cause of ZSD. In addition, this murine model will enhance studies focused on mechanisms of pathogenesis.
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A knock-in mouse model carrying a missense mutation in Pex1 (Pex1-G844D) recapitulates the most frequent mutation in human Zellweger spectrum disorders with a milder pathology.
“Recently also a knock-in mouse model carrying a missense mutation in the Pex1 gene (Pex1-G844D) was reported, which recapitulates the most frequent mutation in the human Zellweger spectrum disorders with a milder pathology [63].”
From Peroxisomes in brain development and function (2016) · cites this paper as [63]
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Peroxisomes in brain development and function
Berger, J., Dorninger, F., Forss-Petter, S., & Kunze, M. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2015.12.005 · Cited by 194 · see citing works
“mutation in the Pex1 gene (Pex1-G844D) was reported, which recapitulates the most frequent mutation in the human Zellweger spectrum disorders with a milder pathology [63].”
BackgroundNano-scale resolution of native retinal rod disk membranes reveals differences in lipid composition
Sander, C. L., Sears, A. E., Pinto, A. F. M., Choi, E. H., Kahremany, S., Gao, F., Salom, D., Jin, H., Pardon, E., Suh, S., et al. (2021) · Journal of Cell Biology · doi:10.1083/jcb.202101063 · Cited by 36 · see citing works
- Authors
- Hiebler, S., Masuda, T., Hacia, J. G., Moser, A. B., Faust, P. L., Liu, A., Chowdhury, N., Huang, N., Lauer, A., Bennett, J., Watkins, P. A., Zack, D. J., Braverman, N. E., Raymond, G. V., & Steinberg, S. J.
- Affiliations
- Kennedy Krieger Institute (US)
- Johns Hopkins University (US)
- University of Southern California (US)
- Columbia University (US)
- University of Pennsylvania (US)
- Institut de la Vision (FR)
- Montreal Children's Hospital (CA)
- Corresponding author
- Steinberg, Steven J.
- ORCID
- Venue
- Molecular Genetics and Metabolism
- Publisher
- Elsevier BV
- Published
- 2014-04
- Volume
- 111
- Issue
- 4
- Pages
- 522-532
- ISSN
- 1096-7192 (ISSN-L)
- PMC
- PMC4901203
- OpenAlex
- W2013220761
- Cited by
- 60
- References
- 63
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 2 · 2023: 5 · 2022: 2 · 2021: 9 · 2020: 7 · 2019: 4 · 2018: 5 · 2017: 8 · 2016: 1 · 2015: 6 · 2014: 1
- FWCI
- 3.67
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Genetics and Metabolism (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (R01EY009769, 5P30EY001765)
- Foundation Fighting Blindness
- Research to Prevent Blindness
- Guerrieri Family Foundation
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Keywords
- Zellweger spectrum disorder, PEX1, missense mutations, peroxisome biogenesis disorders, knock-in mice, retinopathy, cholestasis, hepatic steatosis, growth retardation, peroxisomal beta-oxidation, intellectual disability, failure to thrive, sensory impairment
- MeSH terms
- ATPases Associated with Diverse Cellular Activities, Adenosine Triphosphatases, Animals, Animals, Newborn, Bile Acids and Salts, Disease Models, Animal, Fatty Acids, Female, Fibroblasts, Hearing, Heterozygote, Humans, Male, Membrane Proteins, Mice, Mutant Strains, Phenotype, Retina, Sexual Behavior, Animal, Skin, Vision, Ocular, Zellweger Syndrome, Survival Analysis, Molecular Chaperones, Mutation, Missense, Gene Expression Profiling, Growth and Development, Mice
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