Summary
The genetic relationship between 10 patients with clinical manifestations of rhizomelic chondrodysplasia punctata (RCDP) was studied by complementation analysis after somatic cell fusion. Biochemically, 9 out of the 10 patients were characterized by a partial deficiency of acyl-CoA: dihydroxyacetone phosphate acyltransferase (DHAP-AT) and an impairment of plasmalogen biosynthesis, phytanate catabolism and the maturation of peroxisomal 3-oxoacyl-CoA thiolase; 3-oxoacyl-CoA thiolase was strongly reduced in the peroxisomes of these patients. Fusion of fibroblasts from these 9 patients with Zellweger fibroblasts resulted in complementation as indicated by the restoration of DHAP-AT activity, plasmalogen biosynthesis, and punctate fluorescence after staining with a monoclonal antibody to peroxisomal thiolase. No complementation was observed after fusion of different combinations of the 9 RCDP cell lines, suggesting that they belong to a single complementation group. The tenth patient was characterized biochemically by a deficiency of DHAP-AT and an impairment of plasmalogen biosynthesis. However, maturation and localization of peroxisomal thiolase were normal. Fusion of fibroblasts from this patient with fibroblasts from the other 9 patients resulted in complementation as indicated by the restoration of plasmalogen biosynthesis. We conclude that mutations in at least two different genes can lead to the clinical phenotype of RCDP.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Balfe A, Hoefler G, Chen WW, Watkins PA (1990) Aberrant subcellular localization of peroxisomal 3-ketoacyl-CoA thiolase in the Zellweger syndrome and rhizomelic chondrodysplasia punctata. Pediatr Res 27:304–310
Bout A, Teunissen Y, Hashimoto T, Benne R, Tager JM (1988) Nucleotide sequence of human peroxisomal 3-oxoacyl-CoA thiolase. Nucleic Acids Res 16:10369
Brul S, Westerveld A, Strijland A, Wanders RJA, Schram AW, Heymans HSA, Schutgens RBH, Van Den Bosch H, Tager JM (1988a) Genetic heterogeneity in the cerebro-hepato-renal (Zellweger) syndrome and other inherited disorders with a generalized impairment of peroxisomal functions: a study using complementation analysis. J Clin Invest 81:1710–1715
Brul S, Wiemer EAC, Westerveld A, Strijland A, Wanders RJA, Schram AW, Heymans HSA, Schutgens RBH, Van Den Bosch H, Tager JM (1988b) Kinetics of the assembly of peroxisomes after fusion of complementary cell lines from patients with the cerebro-hepato-renal (Zellweger) syndrome and related disorders. Biochem Biophys Res Commun 152:1083–1089
Fairbairn LJ, Tanner MJA (1989) Complete cDNA sequence of human foetal liver peroxisomal 3-oxoacyl-CoA thiolase. Nucleic Acids Res 17:3588
Fujiki Y, Rachubinski A, Mortensen RM, Lazarow PB (1985) Synthesis of 3-ketoacyl-CoA thiolase of rat-liver peroxisomes on free polyribosomes as a larger precursor. Biochem J 226:697–704
Furuta S, Hashimoto T, Miura S, Mori M, Tatibana M (1982) Cellfree synthesis of the enzymes of peroxisomal β-oxidation. Biochem Biophys Res Commun 105:639–646
Gould SJ, Keller G-A, Subramani S (1988) Identification of peroxisomal targeting signals located at the carboxy terminus of four peroxisomal proteins. J Cell Biol 107:897–905
Heikoop JC, Van Roermund CWT, Just WW, Ofman R, Schutgens RBH, Heymans HSA, Wanders RJA, Tager JM (1990) Rhizomelic chondrodysplasia punctata: deficiency of 3-oxoacyl-coenzyme A thiolase in peroxisomes and impaired processing of the enzyme. J Clin Invest 86:126–130
Heikoop JC, Van Den Berg M, Strijland A, Weijers PJ, Schutgens RBH, Just WW, Wanders RJA, Tager JM (1991) Peroxisomes of normal morphology but deficient in 3-oxoacyl-CoA thiolase in rhizomelic chondrodysplasia punctata fibroblasts. Biochim Biophys Acta 1097:62–70
Heymans HSA, Oorthuijs JWE, Nelck G, Wanders RJA, Schutgens RBH (1984) Rhizomelic chondrodysplasia punctata. Another peroxisomal disorder. N Engl J Med 313:187–188
Heymans HSA, Oorthuijs JEW, Nelck G, Wanders RJA, Dingemans KP, Schutgens RBH (1986) Peroxisomal abnormalities in rhizomelic chondrodysplasia punctata. J Inherited Metab Dis 9:329–331
Hijikata M, Ishii N, Kagamiyama H, Osumi T, Hashimoto T (1987) Structural analysis of cDNA for rat peroxisomal 3-ketoacyl-CoA thiolase. J Biol Chem 262:8151–8158
Hoefler G, Hoefler S, Watkins PA, Chen WW, Moser A, Baldwin V, McGillivary B, Charrow J, Friedman JM, Rutledge L, Hashimoto T, Moser HW (1988) Biochemical abnormalities in rhizomelic chondrodysplasia punctata. J Pediatr 112:726–733
Laemmli UK (1970) Cleavage of structural protein during the assembly of the head of bacteriophage T4. Nature 227:680–685
Lazarow PB, Moser HW (1989) Disorders of peroxisome biogenesis. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic basis of inherited disease. McGraw-Hill, New York, pp 1479–1509
Poulos A, Sheffield L, Sharp D, Sherwood G, Johnson D, Beckman K, Fellenberg AJ, Wraith JE, Chow CW, Usher S, Singh H (1988) Rhizomelic chondrodysplasia punctata: clinical, pathologic, and biochemical findings in two patients. J Pediatr 113:685–690
Roscher AA, Hoefler S, Hoefler G, Paschke E, Paltauf F, Moser A, Moser H (1989) Genetic and phenotypic heterogeneity in disorders of peroxisome biogenesis —a complementation study involving cell lines from 19 patients. Pediatr Res 26:67–72
Schrakamp G, Schalkwijk CG, Schutgens RBH, Wanders RJA, Tager JM, Van Den Bosch H (1988) Plasmalogen biosynthesis in peroxisomal disorders: fatty alcohol versus alkylglycerol. J Lipid Res 29:325–334
Schutgens RBH, Ofman R, Van Den Bosch H, Tager JM, Wanders RJA (1986) Acyl-CoA: dihydroxyacetone phosphate acyltransferase in human skin fibroblasts. Study of its properties using a new assay method. Biochim Biophys Acta 879:286–291
Schutgens RBH, Heymans HSA, Wanders RJA, Oorthuijs JWE, Tager JM, Schrakamp G, Van Den Bosch H, Beemer FA (1988) Multiple peroxisomal enzyme deficiencies in rhizomelic chondrodysplasia punctata. Comparison with Zellweger syndrome, Conradi-Hünermann syndrome and X-linked dominant type of chondrodysplasia punctata. Adv Clin Enzymol 6:57–65
Singh I, Lazo O, Contreras M, Stanley W, Hashimoto T (1991) Rhizomelic chondrodysplasia punctata: biochemical studies of peroxisomes isolated from cultured skin fibroblasts. Arch Biochem Biophys 286:277–283
Smith PK, Krohn RI, Hermanson GT, Mallia AK, Gartner FG, Provenzano MD, Fujimoto EK, Goeke NM, Ason BJ, Klenk DC (1985) Measurement of protein using bicinchoninic acid. Anal Biochem 150:76–85
Spranger JW, Opitz JM, Bidder U (1971) Heterogeneity of chonrodysplasia punctata. Humangenetik 11:190–212
Swinkels BW, Gould SJ, Bodnar AG, Rachubinski RA, Subramani S (1990) Identification of a novel peroxisomal targeting signal in the amino-terminal prepiece of 3-ketoacyl thiolase (abstract). J Cell Biol 111:2146
Wanders RJA, Heymans HSA, Schutgens RBH, Barth PG, Van Den Bosch H, Tager JM (1988) Peroxisomal disorders in neurology. J Neurol Sci 88:1–39
Wiemer EAC, Brul S, Just WW, Van Driel R, Brouwer-Kelder E, Van Den Berg M, Weijers PJ, Schutgens RBH, Van den Bosch H, Schram AW, Wanders RJA, Tager JM (1989) Presence of peroxisomal membrane proteins in liver and fibroblasts from patients with the Zellweger syndrome and related disorders: evidence for the existence of peroxisomal ghosts. Eur J Cell Biol 50:407–417
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Heikoop, J.C., Wanders, R.J.A., Strijland, A. et al. Genetic and biochemical heterogeneity in patients with the rhizomelic form of chondrodysplasia punctata — a complementation study. Hum Genet 89, 439–444 (1992). https://doi.org/10.1007/BF00194319
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00194319