Peroxisomal Bifunctional Protein Deficiency Revisited: Resolution of Its True Enzymatic and Molecular Basis

Abstract

In the past few years, many patients have been described who have a defect of unknown origin in the peroxisomal beta-oxidation pathway. Complementation analysis has been done by various groups to establish the extent of the genetic heterogeneity among the patients. 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. However, molecular analysis of the cDNA encoding l-BP in patients failed to show any mutations. The recent identification of a new d-specific bifunctional protein (d-BP) prompted us to reinvestigate the original patient with presumed l-BP deficiency. 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. Our results suggest that most, if not all, patients whose condition has been diagnosed as l-BP are, in fact, d-BP deficient. 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.

Downregulation of estrogen‐metabolizing 17β‐hydroxysteroid dehydrogenase Type 2 expression correlates inversely with Ki67 proliferation marker in colon‐cancer development

“…12 17HSD type 4 is identical to MFP-2, whose main role is associated with the peroxisomal ␤-oxidation of fatty acids. 30,31 It is therefore more likely that the decrease in oxidative activity converting E2 to E1 in the colon is the result of decreased 17HSD type 2 expression.…”

Mevalonate kinase is a cytosolic enzyme in humans

“…Immunofluorescence was performed as described (van Grunsven et al, 1999). Cells were double labelled with antibodies directed against human MK (Hogenboom et al, 2002) and the peroxisomal marker catalase (Wiemer et al, 1992) or the cytosolic marker metallo matrix protein 7 (MMP7) (MMP-7 Ab-1 (Clone 1D2), Labvision).…”

Studies on the metabolic fate of n-3 polyunsaturated fatty acids

“…The patients with a PBD all had the clinical and biochemical abnormalities described for patients with a PBD, including deficient C26:0, pristanic acid ␤ -oxidation, phytanic acid ␣ -oxidation, and the absence of peroxisomes, as assessed by immunofluorescence microscopy analysis using antibodies against catalase (11). The d -BP-deficient patients all had mutations in the encoding gene, and no enzyme activity could be measured in the fibroblasts of these patients (12)(13)(14). The fibroblasts from patients with a mitochondrial ␤ -oxidation disorder used in this study were from patients with a confirmed deficiency of CACT or MTP due to mutations in the encoding genes [see (15,16) for review].…”