1. Reinvestigation of peroxisomal 3-ketoacyl-CoA thiolase deficiency: identification of the true defect at the level of d-bifunctional protein.
- Author
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Ferdinandusse S, van Grunsven EG, Oostheim W, Denis S, Hogenhout EM, IJlst L, van Roermund CW, Waterham HR, Goldfischer S, and Wanders RJ
- Subjects
- 3-Hydroxyacyl CoA Dehydrogenases chemistry, Amino Acid Sequence, Blotting, Western, Brain enzymology, Brain metabolism, Exons genetics, Fibroblasts, Humans, Hydro-Lyases chemistry, Introns genetics, Kidney enzymology, Kidney metabolism, Multienzyme Complexes chemistry, Peroxisomal Multifunctional Protein-2, Peroxisomes genetics, Zellweger Syndrome enzymology, Zellweger Syndrome metabolism, 17-Hydroxysteroid Dehydrogenases, 3-Hydroxyacyl CoA Dehydrogenases genetics, 3-Hydroxyacyl CoA Dehydrogenases metabolism, Acetyl-CoA C-Acyltransferase deficiency, Enoyl-CoA Hydratase, Hydro-Lyases genetics, Hydro-Lyases metabolism, Multienzyme Complexes genetics, Multienzyme Complexes metabolism, Peroxisomes enzymology
- Abstract
In this report, we reinvestigate the only patient ever reported with a deficiency of peroxisomal 3-ketoacyl-CoA thiolase (THIO). At the time when they were described, the abnormalities in this patient, which included accumulation of very-long-chain fatty acids and the bile-acid intermediate trihydroxycholestanoic acid, were believed to be the logical consequence of a deficiency of the peroxisomal beta-oxidation enzyme THIO. In light of the current knowledge of the peroxisomal beta-oxidation system, however, the reported biochemical aberrations can no longer be explained by a deficiency of this thiolase. In this study, we show that the true defect in this patient is at the level of d-bifunctional protein (DBP). Immunoblot analysis revealed the absence of DBP in postmortem brain of the patient, whereas THIO was normally present. In addition, we found that the patient had a homozygous deletion of part of exon 3 and intron 3 of the DBP gene, resulting in skipping of exon 3 at the cDNA level. Our findings imply that the group of single-peroxisomal beta-oxidation-enzyme deficiencies is limited to straight-chain acyl-CoA oxidase, DBP, and alpha-methylacyl-CoA racemase deficiency and that there is no longer evidence for the existence of THIO deficiency as a distinct clinical entity.
- Published
- 2002
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