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Human PEX7 encodes the peroxisomal PTS2 receptor and is responsible for rhizomelic chondrodysplasia punctata

Nature Geneticsvolume 15pages369376 (1997) | Download Citation



Rhizomelic chondrodysplasia punctata (RCDP) is a rare autosomal recessive phenotype that comprises complementation group 11 of the peroxisome biogenesis disorders (PBD). PEX7, a candidate gene for RCDP identified in yeast, encodes the receptor for peroxisomal matrix proteins with the type-2 peroxisome targeting signal (PTS2). By homology probing we identified human and murine PEX7 genes and found that expression of either corrects the PTS2-import defect characteristic of RCDP cells. In a collection of 36 RCDP probands, we found two inactivating PEX7 mutations: one, L292ter, was present in 26 of the probands, all with a severe phenotype; the second, A218V, was present in three probands, including two with a milder phenotype. A third mutation, G217R, whose functional significance is yet to be determined, was present in five probands, all compound heterozygotes with L292ter. We conclude that PEX7 is responsible for RCDP (PBD CG11) and suggest a founder effect may explain the high frequency of L292ter.

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  1. 1

    Brul, S. et al. Genetic hetrogeneity in the cerebrohepatorenal (Zellweger) syndrome and other inherited disorders with a generalized impairment of peroxisomal functions - A study using complementation analysis. J. Clin. Invest. 81, 1710–1715 (1988).

  2. 2

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

  3. 3

    Moser, A.B. et al. Phenotype of patients with peroxisomal disorders subdivided into sixteen complementation groups. J Pediatr. 127, 13–22 (1995).

  4. 4

    Poulos, A. et al. Peroxisomal assembly defects: Clinical, pathologic and biochemical findings in two patients in a newly identified complementation group. J. Pediatr. 127, 596–599 (1995).

  5. 5

    Lazarow, P.B. & Moser, H.W. . in The Metabolic and Molecular Bases of Inherited Disease. (eds Scriver, C.R. et al.) 2287–2324 (McGraw-Hill, New York, 1995).

  6. 6

    Slawecki, M. et al. Identification of three distinct peroxisomal protein import defects in patients with peroxisome biogenesis disorders. J. Cell Sci. 108, 1817–1829 (1995).

  7. 7

    Hoefler, G. et al. Biochemical abnormalities in rhizomelic chondrodysplasia punctata. J. Pediatr. 112, 726–733 (1988).

  8. 8

    Heikoop, J.C. et al. Rhizomelic chondrodysplasia punctata: Deficiency of 3-oxoacyl-coenzyme A thiolase in peroxisomes and impaired processing of the enzyme. J. Clin. Invest. 86, 126–130 (1990).

  9. 9

    Poll-The, B.T. et al. A new type of chondrodysplasia punctata associated with peroxisomal dysfunction. J. Inher. Metab. Dis. 14, 361–363 (1991).

  10. 10

    Gray, R.G.F. et al. Rhizomelic chondrodysplasia punctata - a new clinical variant. J. Inher. Metab. Dis. 15, 931–932 (1992).

  11. 11

    Nuoffer, J.M. et al. Chondrodysplasia punctata with a mild clinical course. J. Inher. Metab. Dis. 17, 60–66 (1994).

  12. 12

    Barth, P.G., Wanders, R.J.A., Schutgens, R.B.H. & Staalman, C.R. Variant rhizomelic chondrodysplasia punctata (RCDP) with normal plasma phytanic acid: Clinico-biochemical delineation of a subtype and complementation studies. Am. J. Med. Genet. 62, 164–168 (1996).

  13. 13

    Smeitink, J.A.M. et al. Bone dysplasia associated with phytanic acid accumulation and deficient plasmalogen synthesis: A peroxisomal entity amenable to plasmapheresis. J. Inher. Metab. Dis. 15, 377–380 (1992).

  14. 14

    Pike, M.G. et al. Congenital rubella syndrome associated with calcific epiphyseal stippling and peroxisomal dysfunction. J. Pediatr. 116, 88–94 (1990).

  15. 15

    Motley, A.M. et al. Non-rhizomelic and rhizomelic chondrodysplasia punctata within a single complementation group. Biochim. Biophys. Acta. 1315, 153–158 (1996).

  16. 16

    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. Metab. Dis. 15, 389–391 (1992).

  17. 17

    Wanders, R.J.A. et al. Human alkyldihydroxyacetonephosphate synthase deficiency: A new peroxisomal disorder. J. Inher. Metab. Dis. 17, 315–318 (1994).

  18. 18

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

  19. 19

    Kunau, W.H. et al. Two complementary approaches to study peroxisome biogenesis in Saccharomyces cerevisiae: Forward and reversed genetics. Biochimie 75, 209–224 (1993).

  20. 20

    Gould, S.J., McCollum, D., Spong, A.P., Heyman, J.A. & Subramani, S. Development of the yeast Pichia pastoris as a model organism for a genetic and molecular analysis of peroxisome assembly. Yeast 8, 613–628 (1992).

  21. 21

    Purdue, P.E. & Lazarow, P.B. Peroxisomal biogenesis: Multiple pathways of protein import. J. Biol. Chem. 269, 30065–30068 (1994).

  22. 22

    Rachubinski, R.A., Subramani, S. How proteins penetrate peroxisomes. Cell 83, 525–528 (1995).

  23. 23

    Gould, S.J., Keller, G.A., Hosken, N., Wilkinson, J. & Subramani, S. A conserved tripeptide sorts proteins to peroxisomes. J.Cell Biol. 108, 1657–1664 (1989).

  24. 24

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

  25. 25

    Gietl, C., Faber, K.N., van der Klei, I.J. & Veenhuis, M. Mutational analysis of the N-terminal topogenic signal of watermelon glyoxysomal malate dehydrogenase using the heterologous host Hansenula polymorpha. Proc. Natl. Acad. Sci. USA 91, 3151–3155 (1994).

  26. 26

    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).

  27. 27

    Osumi, T. et al. Amino-terminal presequence of the precursor of peroxisomal 3-ketoacyl-CoA thiolase is a cleavable signal peptide for peroxisomal targeting. Biochem. Biophys. Res. Comm. 181, 947–954 (1991).

  28. 28

    Faber, K.N. et al. The N-terminus of amine oxidase of Hansenula polymorpha contains a peroxisomal targeting signal. FEBS Lett. 357, 115–120 (1995).

  29. 29

    Shimozawa, N. et al. A human gene responsible for Zellweger syndrome that affects peroxisome assembly. Science 255, 1132–1134 (1992).

  30. 30

    Dodt, G. et al. Mutations in the PTS1 receptor gene, PXR1 receptor gene, PXR1, define complementation group 2 of the peroxisome biogenesis disorders. Nature Genet.. 9, 115–124 (1995).

  31. 31

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

  32. 32

    Fransen, M. et al. Identification and characterization of the putative human peroxisomal C-terminal targeting signal import receptor. J. Biol. Chem. 270, 7731–7736 (1995).

  33. 33

    Marynen, P., Fransen, M., Raeymaekers, P., Mannaerts, G.P. & Van Veldhoven, P.P. The gene for the peroxisomal targeting signal import receptor (PXR1) is located on human chromosome 12p13, flanked by TPl1 and D12S1089. Genomics 30, 366–368 (1995).

  34. 34

    Yahraus, T. et al. The peroxisome biogenesis disorder group 4 gene, PXAAA1, encodes a cytoplasmic ATPase required for stability of the PTS1 receptor. EMBO J. 15, 2914–2923 (1996).

  35. 35

    Fukuda, S. et al. Human peroxisome assembly factor-2 (PAF-2): A gene responsible for Group C peroxisome biogenesis disorder in humans. Am. J. Hum. Genet. 59, 1210–1220 (1996).

  36. 36

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

  37. 37

    Elgersma, Y. et al. The SH3 domain of the Saccharomyces cerevisiae peroxisomal membrane protein Pex13p functions as a docking site for PexSp, a mobile receptor for the import of PT1-containing proteins. J. Cell Biol. 135, 97–109 (1996).

  38. 38

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

  39. 39

    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).

  40. 40

    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).

  41. 41

    Heikoop, J.C. et al. Peroxisomes of normal morphology but deficient in 3-oxoacyl-CoA thiolase in rhizomelic chondrodysplasia punctata fibroblasts. Biochim. Biophys. Acta. 1097, 69–77 (1991).

  42. 42

    Rehling, P. et al. The import receptor for the peroxisomal targeting signal 2 (PTS2) in Saccharomyces cerevisiae is encoded by the AAS7gene. EMBO J. 15, 2901–2913 (1996).

  43. 43

    Zhang, J.W. & Lazarow, P.B. Peblp (Pas7p) is an intraperoxisomal receptor for the NH2-terminal, type 2, peroxisomal targeting sequence of thiolase: Peblp itself is targeted to peroxisomes by an NH2-terminal peptide. J. Cell. Biol. 132, 325–334 (1996).

  44. 44

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

  45. 45

    Dodt, G., Braverman, N., Valle, D. & Gould, S.J. From expressed sequence tags to peroxisome biogenesis disorder genes. New York Acad. Sci. (in the press).

  46. 46

    Hieter, P., Bassett, D.E. & Valle, D. The yeast genome - a common biological currency. Nature Genet. 13, 253–255 (1996).

  47. 47

    Altschul, S.F., Gish, W., Miller, W., Myers, E.W. & Lipman, D.J. Basic local alignment search tool. J. Mol. Biol. 215, 403–410 (1990).

  48. 48

    Kozak, M. Regulation of translation in eukaryotic systems. Annu. Rev. Cell Biol. 8, 197–225 (1992).

  49. 49

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

  50. 50

    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).

  51. 51

    Wall, M.A. et al. The structure of the G protein heterotrimer 1α1γ2. Cell 83, 1047–1058 (1995).

  52. 52

    Adams-Klages, S. et al. FAN, a novel WD-repeat protein, couples the p55 TNF-receptorto neutral sphingomyelinase. Cell 86, 937–947 (1996).

  53. 53

    Henning, K.A. et al. The Cockayne syndrome group A gene encodes a WD repeat protein that interacts with CSB protein and a subunit of RNA polymerase II TFIIH. Cell 82, 555–564 (1995).

  54. 54

    Fong, H.K.W. et al. Repetitive segmental structure of the transducin β subunit: Homology with the CDC4 gene and identification of related mRNAs. Proc. Natl. Acad. Sci. USA 83, 2162–2166 (1986).

  55. 55

    Goebl, M. & Yanagida, M. The TPR snap helix: a novel protein repeat motif from mitosis to transcription. TIBS 16, 173–177 (1991).

  56. 56

    Tzamarias, D. & Struhl, K. Functional dissection of the yeast Cyc8-Tup1 transcriptional co-repressor complex. Nature 369, 758–761 (1994).

  57. 57

    Brody, L.C. et al. Ornithine-8-aminotransferase mutations causing gyrate atrophy: Allelic heterogeneity and functional consequences. J. Biol. Chem. 267, 3302–3307 (1992).

  58. 58

    Dietz, H.C. et al. The skipping of constitutive exons in vivo induced by nonsense mutations. Science 259, 680–683 (1993).

  59. 59

    Maquat, L.E. When cells stop making sense: Effects of nonsense codons on RNA metabolism in vertebrate cells. RNA 1, 453–465 (1995).

  60. 60

    Cooper, D.N., Krawszak, M. & Antonarakis, S.E. in The Metabolic and Molecular Bases of Inherited Disease. (eds Scriver, C.R. et al) 259–291 (McGraw Hill, New York, 1995).

  61. 61

    Feinberg, A.P. & Vogelstein, B. A technique for radiolabeling DNA restriction endonuclease fragments to high specific activity. Anal. Biochem. 132, 6–13 (1983).

  62. 62

    Engelhardt, J.F., Steel, G. & Valle, D. Transcriptional analysis of the human ornithine aminotransferase promoter. J. Biol. Chem. 266, 752–758 (1991).

  63. 63

    Sambrook, J., Fritsch, E.F. & Maniatis, T. Molecular Cloning: A Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, (1989).

  64. 64

    Chirgwin, J.M., Przybyla, A.E., MacDonald, R.J. & Rutter, W.J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochem. 18, 5294–5299 (1979).

  65. 65

    Mitchell, G.A. et al. Human ornithine-8-aminotransferase: cDNA cloning and analysis of the structural gene. J. Biol. Chem. 263, 14288–14295 (1988).

  66. 66

    Gartner, J., Moser, H. & Valle, D. Mutations in the 70 kD peroxisomal membrane protein gene in Zellweger syndrome. Nature Genet. 1, 16–23 (1992).

  67. 67

    Innis, M.A., Gelfand, D.H., Sninsky, J.J. & White, T.J. PCR Protocols: A Guide to Methods and Applications.(Academic Press, New York, 1990).

  68. 68

    Evan, G.I., Lewis, G.K., Ramsay, G. & Bishop, J.M. Isolation of monoclonal antibodies specific for human c-myc proto-oncogene product. Mol. Cell Biol. 5, 3610–3616 (1985).

  69. 69

    Gould, S.J., Keller, G.A. & Subramani, S. Identification of a peroxisomal targeting signal at the carboxy terminus of firefly luciferase. J. Cell Biol. 105, 2923–2931 (1987).

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  1. Department of Pediatrics, Johns Hopkins University School of Medicine, 725 N. Wolfe Street, Baltimore, Maryland, 21205, USA

    • Nancy Braverman
    • , Gary Steel
    •  & David Valle
  2. Howard Hughes Medical Institute, Johns Hopkins University School of Medicine, 725 N. Wolfe Street, Baltimore, Maryland, 21205, USA

    • Cassandra Obie
    •  & David Valle
  3. Kennedy Krieger Institute, Johns Hopkins University School of Medicine, 725 N. Wolfe Street, Baltimore, Maryland, 21205, USA

    • Ann Moser
    •  & Hugo Moser
  4. Department of Cell Biology and Anatomy, Johns Hopkins University School of Medicine, 725 N. Wolfe Street, Baltimore, Maryland, 21205, USA

    • Stephen J. Gould


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Correspondence to David Valle.

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