Longitudinal study of Pex1-G844D NMRI mouse model: A robust pre-clinical model for mild Zellweger spectrum disorder

Biochimica Et Biophysica Acta. Molecular Basis of Disease
Tanguy DemaretEtienne M Sokal

Abstract

Zellweger spectrum disorders (ZSD) are inborn errors of metabolism caused by mutations in PEX genes that lead to peroxisomal biogenesis disorder (PBD). No validated treatment is able to modify the dismal progression of the disease. ZSD mouse models used to develop therapeutic approaches are limited by poor survival and breeding restrictions. To overcome these limitations, we backcrossed the hypomorphic Pex1 p.G844D allele to NMRI background. NMRI mouse breeding restored an autosomal recessive Mendelian inheritance pattern and delivered twice larger litters. Mice were longitudinally phenotyped up to 6 months of age to make this model suitable for therapeutic interventions. ZSD mice exhibited growth retardation and relative hepatomegaly associated to progressive hepatocyte hypertrophy. Biochemical studies associated with RNA sequencing deciphered ZSD liver glycogen metabolism alterations. Affected fibroblasts displayed classical immunofluorescence pattern and biochemical alterations associated with PBD. Plasma and liver showed very long-chain fatty acids, specific oxysterols and C27 bile acids intermediates elevation in ZSD mice along with a specific urine organic acid profile. With ageing, C26 fatty acid and phytanic acid levels...Continue Reading

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Citations

Jan 24, 2021·Molecular Genetics and Metabolism·João LeandroSander M Houten
Jul 10, 2021·Reviews in Endocrine & Metabolic Disorders·Rubén EscribáÁngel Raya

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