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: S Ferdinandusse, E G van Grunsven, W Oostheim, S Denis, E M Hogenhout, L IJlst, C W T van Roermund, H R Waterham, S Goldfischer, R J A Wanders
• Journal: American journal of human genetics (Am J Hum Genet) Vol. 70 Issue 6 Pg. 1589-93 (Jun 2002) ISSN: 0002-9297 [Print] United States
• PMID: 11992265 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Multienzyme Complexes
• 17-Hydroxysteroid Dehydrogenases
• 3-Hydroxyacyl CoA Dehydrogenases
• Acetyl-CoA C-Acyltransferase
• Hydro-Lyases
• Peroxisomal Multifunctional Protein-2
• HSD17B4 protein, human
• Enoyl-CoA Hydratase

Topics

• 17-Hydroxysteroid Dehydrogenases
• 3-Hydroxyacyl CoA Dehydrogenases (chemistry, genetics, metabolism)
• Acetyl-CoA C-Acyltransferase (deficiency)
• Amino Acid Sequence
• Blotting, Western
• Brain (enzymology, metabolism)
• Enoyl-CoA Hydratase
• Exons (genetics)
• Fibroblasts
• Humans
• Hydro-Lyases (chemistry, genetics, metabolism)
• Introns (genetics)
• Kidney (enzymology, metabolism)
• Multienzyme Complexes (chemistry, genetics, metabolism)
• Peroxisomal Multifunctional Protein-2
• Peroxisomes (enzymology, genetics)
• Zellweger Syndrome (enzymology, metabolism)