Format

Send to

Choose Destination
Mol Genet Metab. 2014 Apr;111(4):522-532. doi: 10.1016/j.ymgme.2014.01.008. Epub 2014 Jan 23.

The Pex1-G844D mouse: a model for mild human Zellweger spectrum disorder.

Author information

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
Departments of Molecular Biology and Genetics, and Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
10
Institut de la Vision, Université Pierre et Marie Curie, Paris, France.
11
Department of Genetics, McGill University, Montreal, Quebec, Canada.
12
Department of Pediatrics, Montreal Children's Hospital, Montreal, Quebec, Canada.
#
Contributed equally

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.

KEYWORDS:

Bile acids; PEX1; Peroxisome; Photoreceptor degeneration; Retinopathy; Zellweger spectrum disorder

PMID:
24503136
PMCID:
PMC4901203
DOI:
10.1016/j.ymgme.2014.01.008
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for PubMed Central
Loading ...
Support Center