Intra-hepatic cholestasis; Oxysterol; PEX1 c.2528G>A; PEX1 p.Gly843Asp; Peroxisome biogenesis disorder; Very long-chain fatty acid; Bile Acids and Salts; Membrane Proteins; Oxysterols; Glucose-6-Phosphatase; ATPases Associated with Diverse Cellular Activities; Pex1 protein, mouse; ATPases Associated with Diverse Cellular Activities/genetics; ATPases Associated with Diverse Cellular Activities/metabolism; Alleles; Animals; Bile Acids and Salts/metabolism; Cell Membrane/metabolism; Female; Glucose-6-Phosphatase/metabolism; Hepatocytes/metabolism; Longitudinal Studies; Male; Membrane Proteins/metabolism; Mice; Mice, Inbred C57BL; Oxysterols/metabolism; RNA-Seq; Zellweger Syndrome/genetics; Zellweger Syndrome/metabolism; Cell Membrane; Hepatocytes; Zellweger Syndrome; Molecular Medicine; Molecular Biology
Abstract :
[en] 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.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Demaret, Tanguy ; Université de Liège - ULiège > Faculté de Médecine > Mast. spéc. gén. clin. ; 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
Roumain, Martin; 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
Ambroise, Jérôme; 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
Evraerts, Jonathan; 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
Ravau, Joachim; 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
Bouzin, Caroline; 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
Bearzatto, Bertrand; 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
Gala, Jean-Luc; 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
Stepman, Hedwig; Department of Laboratory Medicine, Ghent University Hospital, 9000 Ghent, Belgium. Electronic address: hedwig.stepman@uzgent.be
Marie, Sandrine; Department of Laboratory Medicine, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium. Electronic address: sandrine.marie@uclouvain.be
Vincent, Marie-Françoise; Department of Laboratory Medicine, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain (UCLouvain), 1200 Brussels, Belgium. Electronic address: marie-francoise.vincent@uclouvain.be
Muccioli, Giulio G; 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
Najimi, Mustapha; 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
Sokal, Etienne M; 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
The authors thank Michele de Beukelaer, Aur?lie Daumerie, Tamah Abderrahman, Philippine Debeyne and Anniek Van Landschoot for excellent technical assistance. We are indebted to Pr Isabelle Leclercq for numerous pathological comments on liver slides, to Janne Tys for mouse embryonic fibroblasts isolation training, to Dr. Nicolas van Baren for fluorescent scanning expertise and to Pr Philippe Lysy who provided glucometer & strips. Tanguy Demaret is a FRIA Grant Holder from the Fonds De La Recherche Scientifique - FNRS. The funding source had no involvement in the publication process. All experiments were carried out in accordance with the EU Directive 2010/63/EU for animal experiments and approved by the Ethical Committee for Animal Experimentation at the Health Science Sector, UCLouvain, Brussels, Belgium (2017/UCL/MD/006).Tanguy Demaret is a FRIA Grant Holder from the Fonds De La Recherche Scientifique - FNRS . The funding source had no involvement in the publication process.
Vasiljevic, E., Ye, Z., Pavelec, D.M., Darst, B.F., Engelman, C.D., Baker, M.W., Carrier frequency estimation of Zellweger spectrum disorder using ExAC database and bioinformatics tools. Genet. Med. 21:9 (2019), 1969–1976.
Waterham, H.R., Ferdinandusse, S., Wanders, R.J., Human disorders of peroxisome metabolism and biogenesis. Biochim. Biophys. Acta 1863 (2016), 922–933.
Klouwer, F.C., Berendse, K., Ferdinandusse, S., Wanders, R.J., Engelen, M., Poll-The, B.T., Zellweger spectrum disorders: clinical overview and management approach. Orphanet journal of rare diseases, 10, 2015, 151.
Berendse, K., Engelen, M., Ferdinandusse, S., Majoie, C.B., Waterham, H.R., Vaz, F.M., Koelman, J.H., Barth, P.G., Wanders, R.J., Poll-The, B.T., Zellweger spectrum disorders: clinical manifestations in patients surviving into adulthood. J. Inherit. Metab. Dis. 39 (2016), 93–106.
Vogel, B.H., Bradley, S.E., Adams, D.J., D'Aco, K., Erbe, R.W., Fong, C., Iglesias, A., Kronn, D., Levy, P., Morrissey, M., Orsini, J., Parton, P., Pellegrino, J., Saavedra-Matiz, C.A., Shur, N., Wasserstein, M., Raymond, G.V., Caggana, M., Newborn screening for X-linked adrenoleukodystrophy in New York State: diagnostic protocol, surveillance protocol and treatment guidelines. Mol. Genet. Metab. 114 (2015), 599–603.
R.J. Wanders, F.C. Klouwer, S. Ferdinandusse, H.R. Waterham, B.T. Poll-The, Clinical and laboratory diagnosis of peroxisomal disorders, Methods in molecular biology (Clifton, N.J.), 1595 (2017) 329–342.
Waterham, H.R., Ebberink, M.S., Genetics and molecular basis of human peroxisome biogenesis disorders. Biochim. Biophys. Acta 1822 (2012), 1430–1441.
Korman, S.H., Mandel, H., Gutman, A., Characteristic urine organic acid profile in peroxisomal biogenesis disorders. J. Inherit. Metab. Dis. 23 (2000), 425–428.
Rocchiccioli, F., Aubourg, P., Bougneres, P.F., Medium- and long-chain dicarboxylic aciduria in patients with Zellweger syndrome and neonatal adrenoleukodystrophy. Pediatr. Res. 20 (1986), 62–66.
I. De Biase, S. Tortorelli, L. Kratz, J.S. S, K. Cusmano-Ozog, N. Braverman, Laboratory diagnosis of disorders of peroxisomal biogenesis and function: a technical standard of the American College of Medical Genetics and Genomics (ACMG), Genetics in medicine: official journal of the American College of Medical Genetics, (2019).
Braverman, N.E., Raymond, G.V., Rizzo, W.B., Moser, A.B., Wilkinson, M.E., Stone, E.M., Steinberg, S.J., Wangler, M.F., Rush, E.T., Hacia, J.G., Bose, M., Peroxisome biogenesis disorders in the Zellweger spectrum: an overview of current diagnosis, clinical manifestations, and treatment guidelines. Mol. Genet. Metab. 117 (2016), 313–321.
Sokal, E.M., Smets, F., Bourgois, A., Van Maldergem, L., Buts, J.P., Reding, R., Bernard Otte, J., Evrard, V., Latinne, D., Vincent, M.F., Moser, A., Soriano, H.E., Hepatocyte transplantation in a 4-year-old girl with peroxisomal biogenesis disease: technique, safety, and metabolic follow-up. Transplantation 76 (2003), 735–738.
Van Maldergem, L., Moser, A.B., Vincent, M.F., Roland, D., Reding, R., Otte, J.B., Wanders, R.J., Sokal, E., Orthotopic liver transplantation from a living-related donor in an infant with a peroxisome biogenesis defect of the infantile Refsum disease type. J. Inherit. Metab. Dis. 28 (2005), 593–600.
Demaret, T., Varma, S., Stephenne, X., Smets, F., Scheers, I., Wanders, R., Van Maldergem, L., Reding, R., Sokal, E., Living-donor liver transplantation for mild Zellweger spectrum disorder: up to 17 years follow-up. Pediatr. Transplant., 22(3), 2018, e13112.
Baes, M., Van Veldhoven, P.P., Mouse models for peroxisome biogenesis defects and beta-oxidation enzyme deficiencies. Biochim. Biophys. Acta 1822 (2012), 1489–1500.
Baes, M., Gressens, P., Baumgart, E., Carmeliet, P., Casteels, M., Fransen, M., Evrard, P., Fahimi, D., Declercq, P.E., Collen, D., van Veldhoven, P.P., Mannaerts, G.P., A mouse model for Zellweger syndrome. Nat. Genet. 17 (1997), 49–57.
Faust, P.L., Hatten, M.E., Targeted deletion of the PEX2 peroxisome assembly gene in mice provides a model for Zellweger syndrome, a human neuronal migration disorder. J. Cell Biol. 139 (1997), 1293–1305.
Maxwell, M., Bjorkman, J., Nguyen, T., Sharp, P., Finnie, J., Paterson, C., Tonks, I., Paton, B.C., Kay, G.F., Crane, D.I., Pex13 inactivation in the mouse disrupts peroxisome biogenesis and leads to a Zellweger syndrome phenotype. Mol. Cell. Biol. 23 (2003), 5947–5957.
A. Peeters, P. Fraisl, S. van den Berg, E. Ver Loren van Themaat, A. Van Kampen, M.H. Rider, H. Takemori, K.W. van Dijk, P.P. Van Veldhoven, P. Carmeliet, M. Baes, Carbohydrate metabolism is perturbed in peroxisome-deficient hepatocytes due to mitochondrial dysfunction, AMP-activated protein kinase (AMPK) activation, and peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) suppression, The Journal of biological chemistry, 286 (2011) 42162–42179.
B.T. Poll-The, J. Gootjes, M. Duran, J.B. De Klerk, L.J. Wenniger-Prick, R.J. Admiraal, H.R. Waterham, R.J. Wanders, P.G. Barth, Peroxisome biogenesis disorders with prolonged survival: phenotypic expression in a cohort of 31 patients, American journal of medical genetics. Part A, 126a (2004) 333–338.
Berendse, K., Boek, M., Gijbels, M., Van der Wel, N.N., Klouwer, F.C., van den Bergh-Weerman, M.A., Shinde, A.B., Ofman, R., Poll-The, B.T., Houten, S.M., Baes, M., Wanders, R.J.A., Waterham, H.R., Liver disease predominates in a mouse model for mild human Zellweger spectrum disorder. Biochimica et biophysica acta. Molecular basis of disease, 2019.
Hiebler, S., Masuda, T., Hacia, J.G., Moser, A.B., Faust, P.L., Liu, A., Chowdhury, N., Huang, N., Lauer, A., Bennett, J., Watkins, P.A., Zack, D.J., Braverman, N.E., Raymond, G.V., Steinberg, S.J., The Pex1-G844D mouse: a model for mild human Zellweger spectrum disorder. Mol. Genet. Metab. 111 (2014), 522–532.
Argyriou, C., Polosa, A., Cecyre, B., Hsieh, M., Di Pietro, E., Cui, W., Bouchard, J.F., Lachapelle, P., Braverman, N., A longitudinal study of retinopathy in the PEX1-Gly844Asp mouse model for mild Zellweger spectrum disorder. Exp. Eye Res., 107713, 2019.
G.E. Truett, P. Heeger, R.L. Mynatt, A.A. Truett, J.A. Walker, M.L. Warman, Preparation of PCR-quality mouse genomic DNA with hot sodium hydroxide and tris (HotSHOT), BioTechniques, 29 (2000) 52, 54.
Fiebig, T., Boll, H., Figueiredo, G., Kerl, H.U., Nittka, S., Groden, C., Kramer, M., Brockmann, M.A., Three-dimensional in vivo imaging of the murine liver: a micro-computed tomography-based anatomical study. PLoS One, 7, 2012, e31179.
Sokal, E.M., Mostin, J., Buts, J.P., Liver metabolic zonation in rat biliary cirrhosis: distribution is reverse of that in toxic cirrhosis. Hepatology 15 (1992), 904–908.
S. Orjuela, R. Huang, K.M. Hembach, M.D. Robinson, C. Soneson, ARMOR: an automated reproducible modular workflow for preprocessing and differential analysis of RNA-seq data, G3 (Bethesda, Md.), 9 (2019) 2089–2096.
M.D. Robinson, D.J. McCarthy, G.K. Smyth, edgeR: a bioconductor package for differential expression analysis of digital gene expression data, Bioinformatics (Oxford, England), 26 (2010) 139–140.
N. Aizarani, A. Saviano, Sagar, L. Mailly, S. Durand, J.S. Herman, P. Pessaux, T.F. Baumert, D. Grun, A human liver cell atlas reveals heterogeneity and epithelial progenitors, Nature, 572 (2019) 199–204.
S.A. MacParland, J.C. Liu, X.Z. Ma, B.T. Innes, A.M. Bartczak, B.K. Gage, J. Manuel, N. Khuu, J. Echeverri, I. Linares, R. Gupta, M.L. Cheng, L.Y. Liu, D. Camat, S.W. Chung, R.K. Seliga, Z. Shao, E. Lee, S. Ogawa, M. Ogawa, M.D. Wilson, J.E. Fish, M. Selzner, A. Ghanekar, D. Grant, P. Greig, G. Sapisochin, N. Selzner, N. Winegarden, O. Adeyi, G. Keller, G.D. Bader, I.D. McGilvray, Single cell RNA sequencing of human liver reveals distinct intrahepatic macrophage populations, Nature communications, 9 (2018) 4383.
R. Dobie, J.R. Wilson-Kanamori, B.E.P. Henderson, J.R. Smith, K.P. Matchett, J.R. Portman, K. Wallenborg, S. Picelli, A. Zagorska, S.V. Pendem, T.E. Hudson, M.M. Wu, G.R. Budas, D.G. Breckenridge, E.M. Harrison, D.J. Mole, S.J. Wigmore, P. Ramachandran, C.P. Ponting, S.A. Teichmann, J.C. Marioni, N.C. Henderson, Single-cell transcriptomics uncovers zonation of function in the mesenchyme during liver fibrosis, Cell reports, 29 (2019) 1832–1847.e1838.
Rakhshandehroo, M., Hooiveld, G., Muller, M., Kersten, S., Comparative analysis of gene regulation by the transcription factor PPARalpha between mouse and human. PLoS One, 4, 2009, e6796.
Huang, W., Ma, K., Zhang, J., Qatanani, M., Cuvillier, J., Liu, J., Dong, B., Huang, X., Moore, D.D., Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration. Science 312 (2006), 233–236.
Demaret, T., Courtoy, G.E., Ravau, J., Van Der Smissen, P., Najimi, M., Sokal, E.M., Accurate and live peroxisome biogenesis evaluation achieved by lentiviral expression of a green fluorescent protein fused to a peroxisome targeting signal 1. Histochem. Cell Biol. 153:5 (2020), 295–306.
De Rudder, M., Bouzin, C., Nachit, M., Louvegny, H., Vande Velde, G., Jule, Y., Leclercq, I.A., Automated computerized image analysis for the user-independent evaluation of disease severity in preclinical models of NAFLD/NASH, Laboratory investigation; a journal of technical methods and pathology. 2019.
Passonneau, J.V., Lauderdale, V.R., A comparison of three methods of glycogen measurement in tissues. Anal. Biochem. 60 (1974), 405–412.
Carroll, N.V., Longley, R.W., Roe, J.H., The determination of glycogen in liver and muscle by use of anthrone reagent. J. Biol. Chem. 220 (1956), 583–593.
Sadilkova, K., Gospe, S.M. Jr., Hahn, S.H., Simultaneous determination of alpha-aminoadipic semialdehyde, piperideine-6-carboxylate and pipecolic acid by LC-MS/MS for pyridoxine-dependent seizures and folinic acid-responsive seizures. J. Neurosci. Methods 184 (2009), 136–141.
Mutemberezi, V., Masquelier, J., Guillemot-Legris, O., Muccioli, G.G., Development and validation of an HPLC-MS method for the simultaneous quantification of key oxysterols, endocannabinoids, and ceramides: variations in metabolic syndrome. Anal. Bioanal. Chem. 408 (2016), 733–745.
Guillemot-Legris, O., Mutemberezi, V., Cani, P.D., Muccioli, G.G., Obesity is associated with changes in oxysterol metabolism and levels in mice liver, hypothalamus, adipose tissue and plasma. Sci. Rep., 6, 2016, 19694.
Baes, M., Van Veldhoven, P.P., Hepatic dysfunction in peroxisomal disorders. Biochim. Biophys. Acta 1863 (2016), 956–970.
Goldfischer, S., Moore, C.L., Johnson, A.B., Spiro, A.J., Valsamis, M.P., Wisniewski, H.K., Ritch, R.H., Norton, W.T., Rapin, I., Gartner, L.M., Peroxisomal and mitochondrial defects in the cerebro-hepato-renal syndrome. Science 182 (1973), 62–64.
Scotto, J.M., Hadchouel, M., Odievre, M., Laudat, M.H., Saudubray, J.M., Dulac, O., Beucler, I., Beaune, P., Infantile phytanic acid storage disease, a possible variant of Refsum's disease: three cases, including ultrastructural studies of the liver. J. Inherit. Metab. Dis. 5 (1982), 83–90.
Wangler, M.F., Chao, Y.H., Bayat, V., Giagtzoglou, N., Shinde, A.B., Putluri, N., Coarfa, C., Donti, T., Graham, B.H., Faust, J.E., McNew, J.A., Moser, A., Sardiello, M., Baes, M., Bellen, H.J., Peroxisomal biogenesis is genetically and biochemically linked to carbohydrate metabolism in Drosophila and mouse. PLoS Genet., 13, 2017, e1006825.
Braverman, N.E., Moser, A.B., Functions of plasmalogen lipids in health and disease. Biochim. Biophys. Acta 1822 (2012), 1442–1452.
Wiens, K., Berry, S.A., Choi, H., Gaviglio, A., Gupta, A., Hietala, A., Kenney-Jung, D., Lund, T., Miller, W., Pierpont, E.I., Raymond, G., Winslow, H., Zierhut, H.A., Orchard, P.J., A report on state-wide implementation of newborn screening for X-linked Adrenoleukodystrophy. Am. J. Med. Genet. A 179 (2019), 1205–1213.
Klouwer, F.C.C., Ferdinandusse, S., van Lenthe, H., Kulik, W., Wanders, R.J.A., B.T. Poll-The, Waterham, H.R., Vaz, F.M., Evaluation of C26:0-lysophosphatidylcholine and C26:0-carnitine as diagnostic markers for Zellweger spectrum disorders. J. Inherit. Metab. Dis. 40:6 (2017), 875–881.
Ferdinandusse, S., Denis, S., Faust, P.L., Wanders, R.J., Bile acids: the role of peroxisomes. J. Lipid Res. 50 (2009), 2139–2147.
Gielchinsky, Y., Laufer, N., Weitman, E., Abramovitch, R., Granot, Z., Bergman, Y., Pikarsky, E., Pregnancy restores the regenerative capacity of the aged liver via activation of an mTORC1-controlled hyperplasia/hypertrophy switch. Genes Dev. 24 (2010), 543–548.
Matot, I., Nachmansson, N., Duev, O., Schulz, S., Schroeder-Stein, K., Frede, S., Abramovitch, R., Impaired liver regeneration after hepatectomy and bleeding is associated with a shift from hepatocyte proliferation to hypertrophy. FASEB journal: official publication of the Federation of American Societies for Experimental Biology 31 (2017), 5283–5295.
Shi, Z., Wakil, A.E., Rockey, D.C., Strain-specific differences in mouse hepatic wound healing are mediated by divergent T helper cytokine responses. Proc. Natl. Acad. Sci. U. S. A. 94 (1997), 10663–10668.
Hillebrandt, S., Goos, C., Matern, S., Lammert, F., Genome-wide analysis of hepatic fibrosis in inbred mice identifies the susceptibility locus Hfib1 on chromosome 15. Gastroenterology 123 (2002), 2041–2051.
Faust, P.L., Abnormal cerebellar histogenesis in PEX2 Zellweger mice reflects multiple neuronal defects induced by peroxisome deficiency. J. Comp. Neurol. 461 (2003), 394–413.
Faust, P.L., Kovacs, W.J., Cholesterol biosynthesis and ER stress in peroxisome deficiency. Biochimie 98 (2014), 75–85.
Kovacs, W.J., Tape, K.N., Shackelford, J.E., Wikander, T.M., Richards, M.J., Fliesler, S.J., Krisans, S.K., Faust, P.L., Peroxisome deficiency causes a complex phenotype because of hepatic SREBP/Insig dysregulation associated with endoplasmic reticulum stress. J. Biol. Chem. 284 (2009), 7232–7245.
Matsunami, M., Shimozawa, N., Fukuda, A., Kumagai, T., Kubota, M., Chong, P.F., Kasahara, M., Living-donor liver transplantation from a heterozygous parent for infantile Refsum disease, Pediatrics, 137. 2016.
Berendse, K., Koot, B.G.P., Klouwer, F.C.C., Engelen, M., Roels, F., Lacle, M.M., Nikkels, P.G.J., Verheij, J., B.T. Poll-The, Hepatic symptoms and histology in 13 patients with a Zellweger spectrum disorder. J. Inherit. Metab. Dis. 42:5 (2019), 955–965.
Janssen, A., Gressens, P., Grabenbauer, M., Baumgart, E., Schad, A., Vanhorebeek, I., Brouwers, A., Declercq, P.E., Fahimi, D., Evrard, P., Schoonjans, L., Collen, D., Carmeliet, P., Mannaerts, G., Van Veldhoven, P., Baes, M., Neuronal migration depends on intact peroxisomal function in brain and in extraneuronal tissues. J. Neurosci. 23 (2003), 9732–9741.