![]() Surviving mice showed similar hepatic problems as described for mild ZSD patients, including hepatomegaly, bile duct proliferation, liver fibrosis and mitochondrial alterations. Survival beyond P20 was nearly 100%, but surviving mice showed a marked delay in growth. 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. The first 20 post-natal days (P20) were critical for survival of homozygous Pex1-G844D mice (~20% survival rate). After introducing the Pex1-G844D allele by knock-in, we characterized homozygous Pex1-G844D mice for survival, biochemical parameters, including peroxisomal and mitochondrial functions, organ histology, and developmental parameters. 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. The underlying pathogenesis for the liver disease, however, is not fully understood. Liver disease is a prevalent symptom in ZSD patients. They constitute a clinical continuum from severe early lethal to relatively milder presentations in adulthood. Zellweger spectrum disorders (ZSDs) are autosomal recessive diseases caused by defective peroxisome assembly. We tested this hypothesis in nine patients whose condition was diagnosed as l-BP deficiency on the basis of complementation analysis and found clear-cut mutations in the d-BP cDNA from all patients. Our results suggest that most, if not all, patients whose condition has been diagnosed as l-BP are, in fact, d-BP deficient. In a collaborative effort, we have now found that the true defect in this patient is at the level of the d-BP and not at the level of the l-BP. The recent identification of a new d-specific bifunctional protein (d-BP) prompted us to reinvestigate the original patient with presumed l-BP deficiency. However, molecular analysis of the cDNA encoding l-BP in patients failed to show any mutations. ![]() These studies were based on the use of two established cell lines, one with a deficiency of acyl-CoA oxidase and one with a deficiency of l-bifunctional protein (l-BP), and they showed that most patients belong to the l-BP-deficient group. Complementation analysis has been done by various groups to establish the extent of the genetic heterogeneity among the patients. ![]() In the past few years, many patients have been described who have a defect of unknown origin in the peroxisomal beta-oxidation pathway. ![]()
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