The Pex1-G844D mouse: A model for mild human Zellweger spectrum disorder |
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| Institution: | 1. Department of Neurogenetics, Hugo W. Moser Research Institute at Kennedy Krieger, 707 N. Broadway, Baltimore, MD, USA;2. Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA;3. Department of Biochemistry and Molecular Biology, Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA;4. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA;5. Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY, USA;6. Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA;7. F.M. Kirby Center for Molecular Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA;8. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA;9. Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD, USA;10. Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA;11. Institut de la Vision, Université Pierre et Marie Curie, Paris, France;12. Department of Genetics, McGill University, Montreal, Quebec, Canada;13. Department of Pediatrics, Montreal Children''s Hospital, Montreal, Quebec, Canada;1. KU Leuven - University of Leuven, Department of Pharmaceutical and Pharmacological Sciences, Laboratory of Cell Metabolism, B-3000 Leuven, Belgium;2. Laboratory Genetic Metabolic Diseases, Department of Clinical Chemistry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands;3. Department of Biochemistry, NCCR Chemical Biology, University of Geneva, 1211 Geneva, Switzerland;4. Dept Basic Medical Sciences, UGhent, B-9000 Ghent, Belgium;5. Neurolipid Biology group, Instituto de Biologia Molecular e Celular – IBMC, Instituto de Inovação e Investigação em Saúde, University of Porto, 4200-135 Porto, Portugal;6. VIB-KU Leuven Centre for Cancer Biology, Laboratory of Angiogenesis and Vascular Metabolism, B-3000 Leuven, Belgium;7. KU Leuven - University of Leuven, Department of Cellular and Molecular Medicine, Laboratory for Lipid Biochemistry and Protein Interactions, KU Leuven, B-3000 Leuven, Belgium;1. Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA;2. Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, WI, USA;1. Laboratoire Bio-PeroxIL EA7270, University of Bourgogne Franche-Comté, Dijon, France;2. Aix Marseille Univ, CNRS, INSERM, CIML, Centre d''Immunologie de Marseille-Luminy, Marseille, France;3. Laboratory of Clinical Chemistry, Hospital of Varese, ASST-Settelaghi, Milan, Italy;4. Laboratory of Medical Genetics and Neurogenetics, Foundation IRCCS Istituto Neurologico Carlo Besta, Milan, Italy;5. Centre des Sciences du Goût et de l''Alimentation, AgroSup Dijon, UMR6265/UMRA1324, CNRS, INRA, University of Bourgogne Franche-Comté, Dijon, France;6. INSERM, Dijon, France |
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| Abstract: | 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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