title: Reinvestigation of peroxisomal 3-ketoacyl-CoA thiolase deficiency: identification of the true defect at the level of d-bifunctional protein.
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.
authors: Department of Clinical Chemistry, Emma Children's Hospital, Academic Medical Center, University of Amsterdam, 1100 DE Amsterdam, The Netherlands.
authors: S
authors: S
authors: Ferdinandusse
authors: E G
authors: EG
authors: van Grunsven
authors: W
authors: W
authors: Oostheim
authors: S
authors: S
authors: Denis
authors: E M
authors: EM
authors: Hogenhout
authors: L
authors: L
authors: IJlst
authors: C W T
authors: CW
authors: van Roermund
authors: H R
authors: HR
authors: Waterham
authors: S
authors: S
authors: Goldfischer
authors: R J A
authors: RJ
authors: Wanders
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases; D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D000102:Acetyl-CoA C-Acyltransferase / Q000172:deficiency*; D000595:Amino Acid Sequence; D015153:Blotting, Western; D001921:Brain / Q000201:enzymology / Q000378:metabolism; D004746:Enoyl-CoA Hydratase; D005091:Exons / Q000235:genetics; D005347:Fibroblasts; D006801:Humans; D006836:Hydro-Lyases / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D007438:Introns / Q000235:genetics; D007668:Kidney / Q000201:enzymology / Q000378:metabolism; D009097:Multienzyme Complexes / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D064029:Peroxisomal Multifunctional Protein-2; D020675:Peroxisomes / Q000201:enzymology* / Q000235:genetics; D015211:Zellweger Syndrome / Q000201:enzymology / Q000378:metabolism
chemical_list: D009097:Multienzyme Complexes; D015067:17-Hydroxysteroid Dehydrogenases; D015094:3-Hydroxyacyl CoA Dehydrogenases; D000102:Acetyl-CoA C-Acyltransferase; D006836:Hydro-Lyases; D064029:Peroxisomal Multifunctional Protein-2; C104587:HSD17B4 protein, human; D004746:Enoyl-CoA Hydratase