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

Biochim Biophys Acta Mol Basis Dis. 2020 Nov 01;1866(11):165900. Epub 2020 Jul 18
Tanguy Demaret 1 , Martin Roumain 2 , Jérôme Ambroise 3 , Jonathan Evraerts 4 , Joachim Ravau 5 , Caroline Bouzin 6 , Bertrand Bearzatto 7 , Jean-Luc Gala 8 , Hedwig Stepman 9 , Sandrine Marie 10 , Marie-Françoise Vincent 11 , Giulio G Muccioli 12 , Mustapha Najimi 13 , Etienne M Sokal 14
Tanguy Demaret 1 , Martin Roumain 2 , Jérôme Ambroise 3 , Jonathan Evraerts 4 , Joachim Ravau 5 , Caroline Bouzin 6 , Bertrand Bearzatto 7 , Jean-Luc Gala 8 , Hedwig Stepman 9 , Sandrine Marie 10 , Marie-Françoise Vincent 11 , Giulio G Muccioli 12 , Mustapha Najimi 13 , Etienne M Sokal 14
+ et al

[No authors listed]

Author information
  • 1 Laboratoire d'Hépatologie Pédiatrique et Thérapie Cellulaire, Unité PEDI, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium. Electronic address: tanguy.demaret@uclouvain.be.
  • 2 Bioanalysis and Pharmacology of Bioactive Lipids Research Group (BPBL), Louvain Drug Research Institute (LDRI), Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium. Electronic address: martin.roumain@uclouvain.be.
  • 3 Center for Applied Molecular Technologies (CTMA), Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium. Electronic address: jerome.ambroise@uclouvain.be.
  • 4 Laboratoire d'Hépatologie Pédiatrique et Thérapie Cellulaire, Unité PEDI, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium. Electronic address: jonathan.evraerts@uclouvain.be.
  • 5 Laboratoire d'Hépatologie Pédiatrique et Thérapie Cellulaire, Unité PEDI, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium. Electronic address: joachim.ravau@uclouvain.be.
  • 6 IREC Imaging Platform (2IP), Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium. Electronic address: caroline.bouzin@uclouvain.be.
  • 7 Center for Applied Molecular Technologies (CTMA), Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium. Electronic address: bertrand.bearzatto@uclouvain.be.
  • 8 Center for Applied Molecular Technologies (CTMA), Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium. Electronic address: jean-luc.gala@uclouvain.be.
  • 9 Department of Laboratory Medicine, Ghent University Hospital, 9000 Ghent, Belgium. Electronic address: hedwig.stepman@uzgent.be.
  • 10 Department of Laboratory Medicine, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium. Electronic address: sandrine.marie@uclouvain.be.
  • 11 Department of Laboratory Medicine, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium. Electronic address: marie-francoise.vincent@uclouvain.be.
  • 12 Bioanalysis and Pharmacology of Bioactive Lipids Research Group (BPBL), Louvain Drug Research Institute (LDRI), Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium. Electronic address: giulio.muccioli@uclouvain.be.
  • 13 Laboratoire d'Hépatologie Pédiatrique et Thérapie Cellulaire, Unité PEDI, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium. Electronic address: mustapha.najimi@uclouvain.be.
  • 14 Laboratoire d'Hépatologie Pédiatrique et Thérapie Cellulaire, Unité PEDI, Institut de Recherche Expérimentale et Clinique (IREC), Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium. Electronic address: etienne.sokal@uclouvain.be.

摘要


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 tended to normalize in ZSD mice, as described in patients reaching adulthood. In conclusion, our mouse model recapitulates a mild ZSD phenotype and is suitable for liver-targeted therapies evaluation.

KEYWORDS: Intra-hepatic cholestasis, Oxysterol, PEX1 c.2528G>A, PEX1 p.Gly843Asp, Peroxisome biogenesis disorder, Very long-chain fatty acid