title: The Pex1-G844D mouse: a model for mild human Zellweger spectrum disorder.
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.
authors: Department of Neurogenetics, Hugo W. Moser Research Institute at Kennedy Krieger, 707 N. Broadway, Baltimore, MD, USA.
authors: Shandi
authors: S
authors: Hiebler
authors: Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Tomohiro
authors: T
authors: Masuda
authors: Department of Biochemistry and Molecular Biology, Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors: Joseph G
authors: JG
authors: Hacia
authors: Department of Neurogenetics, Hugo W. Moser Research Institute at Kennedy Krieger, 707 N. Broadway, Baltimore, MD, USA.|Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Ann B
authors: AB
authors: Moser
authors: Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
authors: Phyllis L
authors: PL
authors: Faust
authors: Department of Neurogenetics, Hugo W. Moser Research Institute at Kennedy Krieger, 707 N. Broadway, Baltimore, MD, USA.
authors: Anita
authors: A
authors: Liu
authors: Department of Neurogenetics, Hugo W. Moser Research Institute at Kennedy Krieger, 707 N. Broadway, Baltimore, MD, USA.
authors: Nivedita
authors: N
authors: Chowdhury
authors: Department of Biochemistry and Molecular Biology, Institute for Genetic Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors: Ning
authors: N
authors: Huang
authors: Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Amanda
authors: A
authors: Lauer
authors: F.M. Kirby Center for Molecular Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors: Jean
authors: J
authors: Bennett
authors: Department of Neurogenetics, Hugo W. Moser Research Institute at Kennedy Krieger, 707 N. Broadway, Baltimore, MD, USA.|Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Paul A
authors: PA
authors: Watkins
authors: Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Departments of Molecular Biology and Genetics, and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Institut de la Vision, Université Pierre et Marie Curie, Paris, France.
authors: Donald J
authors: DJ
authors: Zack
authors: Department of Genetics, McGill University, Montreal, Quebec, Canada.|Department of Pediatrics, Montreal Children's Hospital, Montreal, Quebec, Canada.
authors: Nancy E
authors: NE
authors: Braverman
authors: Department of Neurogenetics, Hugo W. Moser Research Institute at Kennedy Krieger, 707 N. Broadway, Baltimore, MD, USA.|Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Gerald V
authors: GV
authors: Raymond
authors: Department of Neurogenetics, Hugo W. Moser Research Institute at Kennedy Krieger, 707 N. Broadway, Baltimore, MD, USA.|Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors: Steven J
authors: SJ
authors: Steinberg
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000251:Adenosine Triphosphatases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001647:Bile Acids and Salts / Q000378:metabolism; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000097:blood; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D020869:Gene Expression Profiling; D048788:Growth and Development; D006309:Hearing; D006579:Heterozygote; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D018832:Molecular Chaperones / Q000378:metabolism; D020125:Mutation, Missense / Q000235:genetics*; D010641:Phenotype; D012160:Retina / Q000473:pathology / Q000503:physiopathology; D012726:Sexual Behavior, Animal; D012867:Skin / Q000473:pathology; D016019:Survival Analysis; D014785:Vision, Ocular; D015211:Zellweger Syndrome / Q000097:blood / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology
chemical_list: D001647:Bile Acids and Salts; D005227:Fatty Acids; D008565:Membrane Proteins; D018832:Molecular Chaperones; D000251:Adenosine Triphosphatases; D000074183:ATPases Associated with Diverse Cellular Activities; C111808:PEX1 protein, human; C495989:Pex1 protein, mouse
keywords: Bile acids; PEX1; Peroxisome; Photoreceptor degeneration; Retinopathy; Zellweger spectrum disorder