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Biochim Biophys Acta Mol Basis Dis. 2019 Oct 1;1865(10):2774-2787. doi: 10.1016/j.bbadis.2019.06.013. Epub 2019 Jun 15.

Liver disease predominates in a mouse model for mild human Zellweger spectrum disorder.

Author information

1
Amsterdam UMC, University of Amsterdam, Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology & Metabolism, the Netherlands; Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Paediatric Neurology, the Netherlands.
2
Amsterdam UMC, University of Amsterdam, Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology & Metabolism, the Netherlands.
3
Department of Molecular Genetics, Cardiovascular Research Institute Maastricht, University of Maastricht, the Netherlands.
4
Amsterdam UMC, University of Amsterdam, Pathology, the Netherlands.
5
Department of Pharmaceutical and Pharmacological Sciences, Laboratory of Cell Metabolism, University of Leuven, Belgium.
6
Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Paediatric Neurology, the Netherlands.
7
Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, USA.
8
Amsterdam UMC, University of Amsterdam, Laboratory Genetic Metabolic Diseases, Amsterdam Gastroenterology & Metabolism, the Netherlands. Electronic address: h.r.waterham@amc.uva.nl.

Abstract

Zellweger spectrum disorders (ZSDs) are autosomal recessive diseases caused by defective peroxisome assembly. They constitute a clinical continuum from severe early lethal to relatively milder presentations in adulthood. Liver disease is a prevalent symptom in ZSD patients. The underlying pathogenesis for the liver disease, however, is not fully understood. We report a hypomorphic ZSD mouse model, which is homozygous for Pex1-c.2531G>A (p.G844D), the equivalent of the most common pathogenic variant found in ZSD, and which predominantly presents with liver disease. After introducing the Pex1-G844D allele by knock-in, we characterized homozygous Pex1-G844D mice for survival, biochemical parameters, including peroxisomal and mitochondrial functions, organ histology, and developmental parameters. The first 20 post-natal days (P20) were critical for survival of homozygous Pex1-G844D mice (~20% survival rate). Lethality was likely due to a combination of cholestatic liver problems, liver dysfunction and caloric deficit, probably as a consequence of defective bile acid biosynthesis. Survival beyond P20 was nearly 100%, but surviving mice showed a marked delay in growth. Surviving mice showed similar hepatic problems as described for mild ZSD patients, including hepatomegaly, bile duct proliferation, liver fibrosis and mitochondrial alterations. Biochemical analyses of various tissues showed the absence of functional peroxisomes accompanied with aberrant levels of peroxisomal metabolites predominantly in the liver, while other tissues were relatively spared. ur findings show that homozygous Pex1-G844D mice have a predominant liver disease phenotype, mimicking the hepatic pathology of ZSD patients, and thus constitute a good model to study pathogenesis and treatment of liver disease in ZSD patients.

KEYWORDS:

Bile acid synthesis; Cholestasis; Metabolism; Peroxisome; Peroxisome biogenesis disorder; Zellweger syndrome

PMID:
31207289
DOI:
10.1016/j.bbadis.2019.06.013
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