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

Area of Science:

• Genetics and Molecular Biology
• Developmental Biology
• Biochemistry

Background:

• Zellweger spectrum disorder (ZSD) is a group of inherited diseases caused by defects in PEX genes, crucial for peroxisome assembly.
• The PEX1-G843D allele is a common mutation associated with milder ZSD phenotypes, impacting development and organ function.
• Current therapeutic strategies for ZSD are limited, necessitating better models for drug discovery.

Purpose of the Study:

• To create and validate a novel mouse model (Pex1-G844D) representing the common human PEX1-G843D mutation in Zellweger spectrum disorder.
• To assess the utility of this mouse model for studying ZSD pathogenesis and evaluating potential therapeutic interventions.
• To investigate the cellular and physiological consequences of the Pex1-G844D mutation in mice.

Main Methods:

• Generation of a Pex1-G844D knock-in mouse model.
• Phenotypic characterization including growth, liver function, and sensory deficits (retinopathy).
• In vitro studies using mouse cells and patient-derived fibroblasts to assess response to therapeutic compounds.

Main Results:

• Pex1-G844D homozygous mice exhibit growth retardation and fatty liver with cholestasis, mirroring mild ZSD phenotypes.
• The mouse model displays retinopathy with cone photoreceptor cell death, consistent with human ZSD patient observations.
• Murine cells with the Pex1-G844D mutation respond to chaperone-like compounds, normalizing peroxisomal beta-oxidation, similar to patient cells.

Conclusions:

• The Pex1-G844D mouse is a valuable preclinical model for testing therapies targeting the most frequent genetic cause of ZSD.
• This model will facilitate research into the pathogenic mechanisms underlying ZSD.
• The findings support the development of chaperone-based therapies for ZSD patients with the PEX1-G843D allele.