Rhizomelic chondrodysplasia punctata is a peroxisomal protein targeting disease caused by a non-functional PTS2 receptor

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Rhizomelic chondrodysplasia punctata (RCDP) is an autosomal recessive disease characterized clinically by a disproportionately short stature primarily affecting the proximal parts of the extremities, typical dysmorphic facial appearance, congenital contractures and severe growth and mental retardation. Although some patients have single enzyme deficiencies, the majority of RCDP patients (86%) belong to a single complementation group (CG11, also known as complementation group I, Amsterdam nomenclature1). Cells from CG11 show a tetrad of biochemical abnormalities: a deficiency of i) dihydroxyacetonephosphate acyltransferase, ii) alkyldihydroxyacetonephosphate synthase, iii) phytanic acid α-oxidation and iv) inability to import peroxisomal thiolase. These deficiencies indicate involvement of a component required for correct targeting of these peroxisomal proteins. Deficiencies in peroxisomal targeting are also found in Saccharomyces cerevisiae pex5 and pex7 mutants2–6, which show differential protein import deficiencies corresponding to two peroxisomal targeting sequences (PTS1 and PTS2). These mutants lack their PTS1 and PTS2 receptors, respectively. Like S. cerevisiae pex7 cells, RCDP cells from CG11 cannot import a PTS2 reporter protein7. Here we report the cloning of PEX7 encoding the human PTS2 receptor, based on its similarity to two yeast orthologues. All RCDP patients from CG11 with detectable PEX7 mRNA were found to contain mutations in PEX7. A mutation resulting in C-terminal truncation of PEX7 cosegregates with the disease and expression of PEX7 in RCDP fibroblasts from CG11 rescues the PTS2 protein import deficiency. These findings prove that mutations in PEX7 cause RCDP,CG11.

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  1. 1

    Shimozawa, N. et al. Standardization of complemention grouping of peroxisome-deficient disorders and the second Zellweger patient with peroxisomal assembly factor-1 (PAF1) defect. Am. J. Hum. Genet. 52, 843–844 (1993).

  2. 2

    Van der Leij, I. et al. Isolation of peroxisome assembly mutants from Saccharomyces cerevisiae with different morphologies using a novel positive selection procedure. 119, 153–162 (1992).

  3. 3

    Van der Leij, I., Franse, M.M., Elgersma, Y., Distel, B. & Tabak, H.F. PAS10p is a tetratricopeptide-repeat protein, which is essential for the import of most matrix proteins into peroxisomes of Saccharomyces cerevisiae. Proc. Natl. Acad. Sci. USA 90, 11782–11786 (1993).

  4. 4

    Marzioch, M., Erdmann, R., Veenhuis, M. & Kunau, W.H. Pas7 encodes a novel yeast member of the WD-40 protein family essential for import of 3-oxoacyl-CoA thiolase, a PTS2-containing protein, into peroxisomes. EMBO J. 13, 4908–4918 (1994).

  5. 5

    Zhang, J.W. & Lazarow, P.B. PEB1 (PAS7) in Saccharomyces cerevisiae encodes a hydrophilic, intra-peroxisomal protein that is a member of the WD repeat family and is essential for the import of thiolase into peroxisomes. J. Cell Biol. 129, 65–80 (1995).

  6. 6

    Distel, B. et al. A unified nomenclature for peroxisome biogenesis factors. J. Cell Biol. 135, 1–3 (1996).

  7. 7

    Motley, A., Hettema, E., Distel, B. & Tabak, H.F. Differential protein import deficiencies in human peroxisome assembly disorders. J. Cell Biol. 125, 755–767 (1994).

  8. 8

    Subramani, S. Protein import into peroxisomes and biogenesis of the organelle. Annu. Rev. Cell Biol. 9, 445–478 (1993).

  9. 9

    Lazarow, P.B. & Moser, H.W. . in The Metabolic and Molecular Bases of Inherited Diseases (eds Scriver, C.R., Beaudet, A.L., Sly, W.S. & Valle, D.) 2287–2325 (McGraw-Hill, New York, 1995).

  10. 10

    Elgersma, Y. & Tabak, H.F. Proteins involved in peroxisome biogenesis and functioning. Biochim. Biophys. Acta. 1996, 269–283 (1996).

  11. 11

    De Hoop, M.J. & Ab, G. Import of proteins into peroxisomes and other microbodies. Bioch. J. 286, 657–669 (1992).

  12. 12

    Elgersma, Y. et al. Analysis of the carboxyl-terminal peroxisomal targeting signal 1 in a homologous context in Saccharomyces cerevisiae. J. Biol. Chem. 271, 26375–26382 (1996).

  13. 13

    McCollum, D., Monosov, E. & Subramani, S. The pas8 mutant of Pichia pastoris exhibits the peroxisomal protein import deficiencies of Zellweger syndrome cells: the PASS protein binds to the COOH-terminal tripeptide peroxisomal targeting signal, and is a member of the TPR protein family. J. Cell Biol. 121, 761–774 (1993).

  14. 14

    Van der Klei, I.J. et al. The Hansenula polymorpha PER3 gene is essential for the import of PTS1 proteins into the peroxisomal matrix. J. Biol. Chem. 270, 17229–17236 (1995).

  15. 15

    Rehling, P. et al. The import receptor for the peroxisomal targeting signal 2 (PTS2) in Saccharomyces cerevisiae is encoded by the PAS7 gene. EMBO J. 15, 2901–2913 (1996).

  16. 16

    Elgersma, Y. et al. The SH3 domain of the Saccharomyces cerevisiae peroxisomal membrane protein Pex13p functions as a docking site for Pex5p, a mobile receptor for the import of PTS1-containing proteins. J. Cell Biol. 135, 97–109 (1996).

  17. 17

    Gould, S.J. et al. Pex13p is an SH3 protein of the peroxisomal membrane and a docking factor for the predominantly cytoplasmic PTS1 receptor. J. Cell Biol. 135, 85–95 (1996).

  18. 18

    Dodt, G. & Gould, S.J. Multiple PEX genes are required for proper subcellular distribution and stability of Pex5p, the PTS1 receptor: evidence that PTS1 protein import is mediated by a cycling receptor. J. Cell Biol. 135, 1763–1774 (1996).

  19. 19

    Dodt, G. et al. Mutations in the PTS1 receptor gene, PXR1, define complementation group 2 of the peroxisome biogenesis disorders. Nature Genet. 9, 115–125 (1995).

  20. 20

    Wiemer, E.A. et al. Human peroxisome targeting signal-1 receptor retores peroxisomal protein import in cells from patients with fatal peroxisome disorders. J. Cell Biol. 130, 51–65 (1995).

  21. 21

    Neer, E.J., Schmidt, C.J., Nambudripad, R. & Smith, T.F. The ancient regulatory protein family of WD-repeat proteins. Nature 371, 297–300 (1994).

  22. 22

    Van der Voorn, L. & Ploegh, H.L. The WD-40 repeat. FEBS Lett. 307, 131–134 (1992).

  23. 23

    Zhang, J.W. & Lazarow, P.B. Peblp (Pas7p) is an intraperoxisomal receptor for the NH2-targeting sequence of thiolase: Peblp itself is targeted to peroxisomes by an NH2-terminal peptide. J. Cell Biol. 132, 325–334 (1996).

  24. 24

    Erdmann, R. & Blobel, G. Identification of Pex13p, a peroxiomal membrane receptor for the PTS1 recognition factor. J. Cell Biol. 135, 111–121 (1996).

  25. 25

    Wanders, R.J.A., Schumacher, H., Heikoop, J., Schutgens, R.B.H. & Tager, J.M. Human dihydroxyacetonephosphate acyltransferase deficiency: a new peroxisomal disorder. J. Inher. Metabol. Dis. 15, 389–391 (1992).

  26. 26

    Wanders, R.J.A. et al. Human alkyldihydroxyacetonephosphatesynthase deficiency: A new peroxisomal disorder. J. Inher. Metab. Dis. 17, 315–318 (1993).

  27. 27

    Tsukamoto, T., Miura, S. & Fujiki, Y. Restoration by a 35K membrane protein of peroxisome assembly in a peroxisome-deficient mammalian cell mutant. Nature 350, 77–81 (1991).

  28. 28

    Yahraus, T. et al. The peroxisome biogenesis disorder group 4 gene, PXAAA1, encodes a cytoplasmic ATPase required for stability of the PTS-1 receptor. EMBO J. 15, 2914–2923 (1996).

  29. 29

    Tsukamoto, T. et al. Peroxisome assembly factor 2, a putative ATPase cloned by functional complementation of a peroxisome-deficient mammalian cell mutant. Nature Genet. 11, 395–401 (1995).

  30. 30

    Amara, J.F., Cheng, S.H. & Smith, A.E. Intracellular protein trafficking defects in human disease. Trends Cell Biol. 2, 145–149 (1992).

  31. 31

    Heus, J.J., Zonneveld, B.J.M., Steensma, H.Y. & Van den Berg, J.A. Centromeric DNA of Kluyveromyces lactis . Curr. Genet. 18, 517–522 (1990).

  32. 32

    Ijlst, L., Wanders, R.J.A., Ushikubo, S., Kamijo, T. & Hashimoto, T. Molecular basis of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: identification of the major disease causing mutation in the α-subunit of the mitochondria! trifunctional protein. Biochim. Biophys. Acta. 1215, 347–350 (1994).

  33. 33

    Swinkels, B.W., Gould, S.J., Bodnar, A.G., Rachubinski, R.A. & Subramani, S. A novel, cleavable peroxisomal targeting signal at the amino-terminus of the rat 3-ketoacyl-CoA thiolase.EMBO J. 10, 3255–3262 (1991).

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Correspondence to Henk F. Tabak or Ronald J.A. Wanders.

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