TY - JOUR
T1 - Liver disease predominates in a mouse model for mild human Zellweger spectrum disorder
AU - Berendse, Kevin
AU - Boek, Maxim
AU - Gijbels, Marion
AU - Van der Wel, Nicole N.
AU - Klouwer, Femke C.
AU - van den Bergh-Weerman, Marius A.
AU - Shinde, Abhijit Babaji
AU - Ofman, Rob
AU - Poll-The, Bwee Tien
AU - Houten, Sander M.
AU - Baes, Myriam
AU - Wanders, Ronald J. A.
AU - Waterham, Hans R.
N1 - Funding Information:
We thank Merel Ebberink for helpful discussions and Petra Mooijer and Wicky Tigchelaar for valuable contributions to the paper. This work was supported by research grants from Hersenstichting Nederland (grant number F2012(1)-102 ) and E-Rare-3 PERescue (ZonMW # 9 003037605 ) to H.R.W., Stichting Steun Emma Kinderziekenhuis AMC (grant nr WAR012-2015-03-003 ) to B.T.P-T and Stichting Metakids (grant nr 2014-049 ) to B.T.P-T and H.R.W.
Funding Information:
We thank Merel Ebberink for helpful discussions and Petra Mooijer and Wicky Tigchelaar for valuable contributions to the paper. This work was supported by research grants from Hersenstichting Nederland (grant number F2012(1)-102) and E-Rare-3 PERescue (ZonMW # 9003037605) to H.R.W. Stichting Steun Emma Kinderziekenhuis AMC (grant nr WAR012-2015-03-003) to B.T.P-T and Stichting Metakids (grant nr 2014-049) to B.T.P-T and H.R.W.
Publisher Copyright:
© 2019 The Authors
PY - 2019/10/1
Y1 - 2019/10/1
N2 - 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 mitochondria) functions, organ histology, and developmental parameters. The first 20 post-natal days (P20) were critical for survival of homozygous Pex1-G844D mice (similar to 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.
AB - 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 mitochondria) functions, organ histology, and developmental parameters. The first 20 post-natal days (P20) were critical for survival of homozygous Pex1-G844D mice (similar to 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.
KW - Peroxisome biogenesis disorder
KW - Peroxisome
KW - Metabolism
KW - Zellweger syndrome
KW - Bile acid synthesis
KW - Cholestasis
KW - PEROXISOME-BIOGENESIS
KW - BETA-OXIDATION
KW - CLINICAL-MANIFESTATIONS
KW - FATTY-ACIDS
KW - MITOCHONDRIAL
KW - DIAGNOSIS
KW - MICE
KW - DYSFUNCTION
KW - PATHOLOGY
KW - DEFECTS
U2 - 10.1016/j.bbadis.2019.06.013
DO - 10.1016/j.bbadis.2019.06.013
M3 - Article
C2 - 31207289
SN - 0925-4439
VL - 1865
SP - 2774
EP - 2787
JO - Biochimica et Biophysica Acta-Molecular Basis of Disease
JF - Biochimica et Biophysica Acta-Molecular Basis of Disease
IS - 10
ER -