title: Rhizomelic chondrodysplasia punctata. Deficiency of 3-oxoacyl-coenzyme A thiolase in peroxisomes and impaired processing of the enzyme.
abstract: The rhizomelic form of chondrodysplasia punctata (RCDP) is a peroxisomal disorder characterized biochemically by an impairment of plasmalogen biosynthesis and phytanate catabolism. We have now found that the maturation of peroxisomal 3-oxoacyl-CoA thiolase is impaired in fibroblasts from RCDP patients. To establish the subcellular localization of the 3-oxoacyl-CoA thiolase precursor protein, cultured skin fibroblasts were fractionated on a continuous Nycodenz gradient. Only a small amount of 3-oxoacyl-CoA thiolase activity was present in the catalase-containing (peroxisomal) fractions of RCDP fibroblasts in comparison with control fibroblasts. Moreover, the amount of thiolase protein in immunoblots of the catalase-containing fractions was below the limit of detection. Finally, the beta-oxidation of [14C]palmitoyl-CoA was found to be reduced in these fractions. We conclude that the mutation in RCDP leads to a partial deficiency of 3-oxoacyl-CoA thiolase activity in the peroxisomes and, concomitantly, an impairment in the ability to convert the precursor of this protein to the mature form. The reduction of 3-oxoacyl-CoA thiolase activity results in a decrease in the rate of peroxisomal beta-oxidation of palmitoyl-CoA. However, the capacity of the peroxisomes to oxidize very-long-chain fatty acids must be sufficient to prevent excessive accumulation of these compounds in vivo.
authors.affiliation: E.C. Slater Institute for Biochemical Research, University of Amsterdam, The Netherlands.
authors.forename: J C
authors.initials: JC
authors.lastname: Heikoop
authors.forename: C W
authors.initials: CW
authors.lastname: van Roermund
authors.forename: W W
authors.initials: WW
authors.lastname: Just
authors.forename: R
authors.initials: R
authors.lastname: Ofman
authors.forename: R B
authors.initials: RB
authors.lastname: Schutgens
authors.forename: H S
authors.initials: HS
authors.lastname: Heymans
authors.forename: R J
authors.initials: RJ
authors.lastname: Wanders
authors.forename: J M
authors.initials: JM
authors.lastname: Tager
mesh_terms: D000102:Acetyl-CoA C-Acyltransferase / Q000172:deficiency*; D000217:Acyltransferases / Q000172:deficiency*; D015153:Blotting, Western; D002451:Cell Compartmentation; D002499:Centrifugation, Density Gradient; D002806:Chondrodysplasia Punctata / Q000201:enzymology*; D005347:Fibroblasts / Q000378:metabolism; D006801:Humans; D008830:Microbodies / Q000201:enzymology*; D010955:Plasmalogens / Q000096:biosynthesis; D011499:Protein Processing, Post-Translational
chemical_list: D010955:Plasmalogens; D000217:Acyltransferases; D000102:Acetyl-CoA C-Acyltransferase