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Rhizomelic Chondrodysplasia Punctata. Deficiency of 3-Oxoacyl- Coenzyme a Thiolase in Peroxisomes and Impaired Processing of the Enzyme

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Rhizomelic Chondrodysplasia Punctata. Deficiency of 3-Oxoacyl- Coenzyme a Thiolase in Peroxisomes and Impaired Processing of the Enzyme Rhizomelic chondrodysplasia punctata. Deficiency of 3-oxoacyl- coenzyme A thiolase in peroxisomes and impaired processing of the enzyme. J C Heikoop, … , R J Wanders, J M Tager J Clin Invest. 1990;86(1):126-130. https://doi.org/10.1172/JCI114674. Research Article 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. Find the latest version: https://jci.me/114674/pdf Rhizomelic Chondrodysplasia Punctata Deficiency of 3-Oxoacyl-Coenzyme A Thiolase in Peroxisomes and Impaired Processing of the Enzyme J. C. Heikoop,* C. W. T. van Roermund,* W. W. Just,* R. Ofman,$ R. B. H. Schutgens,t H. S. A. Heymans,11 R. J. A. Wanders,* and J. M. Tager* *E. C. Slater Institute for Biochemical Research, University ofAmsterdam, Academic Medical Centre, 1105 AZ Amsterdam, The Netherlands; tDepartment of Pediatrics, University Hospital, University ofAmsterdam, 1105 AZ Amsterdam, The Netherlands; lInstitutflir Biochemie I, Medizinische Fakultdt, Universitdt Heidelberg, D-6900 Heidelberg, Federal Republic ofGermany; and lDepartment ofPediatrics, State University Groningen, 9713 EZ Groningen, The Netherlands Abstract The peroxisomal disorders known today can be subdivided into three categories. Diseases such as the cerebro-hepato-renal The rhizomelic form of chondrodysplasia punctata (RCDP) is (Zellweger) syndrome (ZS),' neonatal adrenoleukodystrophy, a peroxisomal disorder characterized biochemically by an im- and infantile Refsum disease are characterized by a decreased pairment of plasmalogen biosynthesis and phytanate catabo- number or absence of morphologically distinguishable peroxi- lism. We have now found that the maturation of peroxisomal somes in liver and other tissues. Multiple biochemical abnor- 3-oxoacyl-CoA thiolase is impaired in fibroblasts from RCDP malities, including impaired ,8-oxidation of very-long-chain patients. fatty acids (VLCFA), decreased, oxidation of phytanic acid and To establish the subcellular localization of the 3-oxoacyl- pipecolic acid, impaired plasmalogen synthesis, and accumu- CoA thiolase precursor protein, cultured skin fibroblasts were lation of intermediates in the biosynthesis of bile acids, are fractionated on a continuous Nycodenz gradient. Only a small observed in these diseases of peroxisome biogenesis (1-3). amount of 3-oxoacyl-CoA thiolase activity was present in the In another group of disorders, including X-linked adreno- catalase-containing (peroxisomal) fractions of RCDP fibro- leukodystrophy (4, 5), hyperoxaluria type 1 (6), acyl-CoA oxi- blasts in comparison with control fibroblasts. Moreover, the dase deficiency (7), bifunctional enzyme deficiency (8), and amount of thiolase protein in immunoblots of the catalase-con- 3-oxoacyl-CoA thiolase deficiency (9), peroxisome structure is taining fractions was below the limit of detection. Finally, the normal and the mutation involves a single peroxisomal en- fl-oxidation of 1'4Cjpalmitoyl-CoA was found to be reduced in zyme. these fractions. In a third group of disorders the activity of more than one We conclude that the mutation in RCDP leads to a partial peroxisomal enzyme is deficient, but the peroxisomal struc- deficiency of 3-oxoacyl-CoA thiolase activity in the peroxi- ture appears to be intact. The rhizomelic form of chondrodys- somes and, concomitantly, an impairment in the ability to con- plasia punctata (RCDP) is one of two examples of such dis- vert the precursor of this protein to the mature form. The orders with an impairment of some, but not all, peroxisomal reduction of 3-oxoacyl-CoA thiolase activity results in a de- functions (10-15). RCDP patients have an impairment in crease in the rate of peroxisomal f-oxidation of palmitoyl- their ability to synthesize plasmalogens due to a deficiency CoA. However, the capacity of the peroxisomes to oxidize of acyl-CoA: dihydroxyacetonephosphate acyltransferase very-long-chain fatty acids must be sufficient to prevent exces- (DHAP-AT) and alkyldihydroxyacetonephosphate synthase sive accumulation of these compounds in vivo. (J. Clin. Invest. (Alkyl-DHAP synthase), the enzymes required for the intro- 1990. 86:126-130.) Key words: fl-oxidation Zellweger syn- duction of the ether bond in etherphospholipids. Furthermore, drome - organelle biogenesis - inborn errors - lipid metabolism there is an accumulation of phytanic acid in body fluids, pre- sumably due to a deficiency of one of the components of the Introduction phytanic acid oxidase system. Finally, recent immunoblotting studies have revealed that peroxisomal 3-oxoacyl-CoA thiolase During the last decade it has become increasingly evident that is present in the unprocessed 44-kD form in liver (13) and peroxisomes play an indispensable role in the metabolism of fibroblasts (14), as is the case in the disorders of peroxisome mammalian cells. The importance of peroxisomes is stressed biogenesis; peroxisomal thiolase, in contrast to most peroxi- by the existence of a number of genetic disorders in man in somal proteins, is synthesized as a larger precursor (16, 17). which one or several peroxisomal functions are impaired (for a However, peroxisomes are present in RCDP, as indicated by review see references 1-3). the fact that the catalase activity in fibroblasts is particle bound (10-14). In RCDP patients there is no accumulation of VLCFA in body fluids, suggesting that peroxisomal fl-oxida- Address correspondence to Dr. J. M. Tager, % Ms. G. E. E. van Nop- of acids is normal. pen, Publications Secretary, E. C. Slater Institute for Biochemical Re- tion fatty search, University of Amsterdam, Meibergdreef 15, 1105 AZ Amster- The aim of the study described in this paper was to obtain dam, The Netherlands. more information about the nature of the defect in RCDP that Receivedfor publication 28 December 1989 and in revisedform 21 February 1990. 1. Abbreviations used in this paper: Alkyl-DHAP synthase, alkyldihy- J. Clin. Invest. droxyacetonephosphate synthase; DHAP-AT, acyl-CoA:dihydroxyac- © The American Society for Clinical Investigation, Inc. etonephosphate acyltransferase; RCDP, rhizomelic chondrodysplasia 0021-9738/90/07/126/05 $2.00 punctata; VLCFA, very-long-chain fatty acids (C > 22); ZS, cerebro- Volume 86, July 1990, 126-130 hepato-renal (Zellweger) syndrome. 126 Heikoop, van Roermund, Just, Ofman, Schutgens, Heymans, Wanders, and Tager leads to a deficient conversion of the precursor of 3-oxoacyl- tanic acid levels are strongly elevated (10-15) and are compa- CoA thiolase to the mature form of the enzyme. Such studies rable to those in ZS (1, 3). In RCDP, in contrast to ZS, normal should provide further insight into the mechanisms involved C26:0/C22:0 fatty acid ratios are found in both plasma (12, 13, in the biogenesis ofperoxisomes. Some ofthe results have been 15) and cultured skin fibroblasts (12-14), suggesting that the reported in abstract form (14). metabolism of VLCFA is not impaired in these patients (see below, however). Methods Finally, the amount of particle-bound catalase is normal in cultured skin fibroblasts from RCDP patients (1 1-14), thus Patients. Cell lines from 13 patients with clinical and biochemical indicating that catalase is contained within particles (peroxi- manifestations characteristic of RCDP were used in these studies (see somes) in RCDP fibroblasts. reference 12 for details). Culture offibroblasts. Skin fibroblasts were grown to confluency, Immunoblot analysis ofperoxisomal 3-oxoacyl-CoA harvested by gentle trypsinization, and collected by centrifugation ex- thiolase in cultured skin fibroblasts actly as described by Wanders et al. (18). Immunoblot experiments were carried out using antibodies Digitonin fractionation of cultured skin fibroblasts. Cultured skin fibroblasts were incubated in isotonic media containing 250 mM su- against peroxisomal 3-oxoacyl-CoA thiolase isolated from rat crose, 20 mM 3-(4-morpholino)propane sulfonic acid (MOPS), pH liver. The results are shown in Fig. 1. In fibroblasts from con- 7.4, 2 mM EDTA, and 125 ,g/ml digitonin. Soluble and sedimentable trol subjects cross-reactive immunological material was pres- fractions were prepared by centrifugation (10,000 gay, 5 min). This ent corresponding to the 41-kD mature form of 3-oxoacyl- concentration of digitonin led
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