Rhizomelic chondrodysplasia punctata. Deficiency of 3-oxoacyl-coenzyme A thiolase in peroxisomes and impaired processing of the enzyme.
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.
Heikoop
J C
JC
E.C. Slater Institute for Biochemical Research, University of Amsterdam, The Netherlands.
van Roermund
C W
CW
Just
W W
WW
Ofman
R
R
Schutgens
R B
RB
Heymans
H S
HS
Wanders
R J
RJ
Tager
J M
JM
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
D010955:Plasmalogens; D000217:Acyltransferases; D000102:Acetyl-CoA C-Acyltransferase