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Identification of PAHX, a Refsum disease gene

Nature Genetics volume 17, pages 185–189 (1997)Cite this article

Abstract

Refsum disease is an autosomal recessive disorder characterized by retinitis pigmentosa, peripheral poly neuropathy, cerebellar ataxia and increased cerebrospinal fluid protein1. Biochemically, the disorder is defined by two related properties: pronounced accumulation of phytanic acid and selective loss of the peroxisomal dioxygenase required for α-hydroxylation of phytanoyl-CoA2. Decreased phytanioacid oxidation is also observed in human cells lacking PEX7, the receptor for the type-2 peroxisomal targeting signal (PTS2; refs 3,4), suggesting that the enzyme defective in Refsum disease is targetted to peroxisomes by a PTS2. We initially identified the human PAHX and mouse Pahx genes as expressed sequence tags (ESTs) capable of encoding PTS2 proteins. Human PAHX is targetted to peroxisomes, requires the PTS2 receptor for peroxisomal localization, interacts with the PTS2 receptor in the yeast two-hybrid assay and has intrinsic phytanoyl-CoA α-hydroxylase activity that requires the dioxygenase cofactor iron and cosubstrate 2-oxoglutarate. Radiation hybrid data place PAHX on chromosome 10 between the markers D10S249 and D10S466, a region previously implicated in Refsum disease by homozygosity mapping5. We find that both Refsum disease patients examined are homozygous for inactivating mutations in PAHX, demonstrating that mutations in PAHX can cause Refsum disease.

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References

  1. Steinberg, D. Refsum disease. in The Metabolic and Molecular Bases of Inherited Disease (eds Scriver, C. R., Beaudet, A.L., Sly, W.S. & Valle, D.) 2351–2369 (McGraw-Hill, New York, 1995).

    Google Scholar 

  2. Mihalik, S.J., Rainville, A.M. & Watkins, P.A. Phytanic acid alpha-oxidation in rat liver peroxisomes: production of alpha-hydroxyphytanoyl-CoA and formate is enhanced by dioxygenase cofactors. Eur. J. Biochem. 232, 545–551 (1995).

    Article  CAS  Google Scholar 

  3. Lazarow, P.B. & Moser, H.W. Disorders of peroxisome biogenesis. in The Metabolic and Molecular Bases of Inherited Disease (eds Scriver, C. R., Beaudet, A.L., Sly, W.S. & Valle, D.) 2287–2324 (McGraw-Hill, New York, 1995).

    Google Scholar 

  4. Braverman, N. et al. Human PEX7 encodes the peroxisomal PTS2 receptor and is responsible for rhizomelic chondrodysplasia punctata. Nature Genet. 15, 369–376 (1997).

    Article  CAS  Google Scholar 

  5. Nadal, N. et al. Localization of Refsum disease with increased pipecolic acidaemia to chromosome 10p by homozygosity mapping and carrier testing in a single nuclear family. Hum. Mol. Genet. 4, 1963–1966 (1995).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  7. 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).

    Article  CAS  Google Scholar 

  8. de Vet, E.C., Zomer, A.W., Lahaut, G.J. & van den Bosch, H. Polymerase chain reaction-based cloning of alkyl-dihydroxyacetonephosphate synthase complementary DNA from guinea pig liver. J. Biol. Chem. 272, 798–803 (1997).

    Article  CAS  Google Scholar 

  9. Hijikata, M., Ishii, N., Kagamiyama, H., Osumi, T. & Hashimoto, T. Structural analysis of cDNA for rat peroxisomal 3-ketoacyl CoA thiolase. J. Biol. Chem. 262, 8151–8158 (1987).

    CAS  PubMed  Google Scholar 

  10. Jansen, G.A., Wanders, R.J.A., Watkins, P.A. & Mihalik, S.J. Phytanoyl–coenzyme A hydroxylase deficiency—the enzyme defect in Refsum's disease (letter). N. Engl. J. Med. 337, 133–134 (1997).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

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

    Article  CAS  Google Scholar 

  14. Gould, S.J., Krisans, S., Keller, G.A. & Subramani, S. Antibodies directed against the peroxisomal targeting signal of firefly luciferase recognize multiple mammalian peroxisomal proteins. J. Cell Biol. 110, 27–34 (1990).

    Article  CAS  Google Scholar 

  15. Fields, S. & Song, O. A novel genetic system to detect protein–protein interactions (letter). Nature 340, 245–246 (1989).

    Article  CAS  Google Scholar 

  16. Watkins, P.A., Howard, A.E., Gould, S.J., Avigan, J. & Mihalik, S.J. Phytanic acid activation in rat liver peroxisomes is catalyzed by long-chain acyl-CoA synthetase. J. Lipid Res. 37, 2288–2295 (1996).

    CAS  PubMed  Google Scholar 

  17. Hudson, T.J. et al. An STS-based map of the human genome. Science 270, 1945–1954 (1995).

    Article  CAS  Google Scholar 

  18. Tranchant, C. et al. A new peroxisomal disease with impaired phytanic and pipecolic acid oxidation. Neurology 43, 2044–2048 (1993).

    Article  CAS  Google Scholar 

  19. Reuber, B.E., Karl, C., Reimann, Mihalik, S.J., & Dodt, G. Cloning and functional expression of a mammalian gene for a peroxisomal sarcosine oxidase. J. Biol. Chem. 272, 6766–6776 (1997).

    Article  CAS  Google Scholar 

  20. 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).

    Article  CAS  Google Scholar 

  21. 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).

    Article  CAS  Google Scholar 

  22. Chang, C.-C., Lee, W.-H., Moser, H., Valle, D. & Gould, S.J. Isolation of the human PEX12 gene, mutated in group 3 of the peroxisome biogenesis disorders. Nature Genet. 15, 385–388 (1997).

    Article  CAS  Google Scholar 

  23. Evan, G.E., 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).

    Article  CAS  Google Scholar 

  24. Michaud, J. et al. Strand-separating conformational polymorphism analysis: efficacy of detection of point mutations in the human ornithine-d-aminotransferase gene. Genomics 13, 389–394 (1992).

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. The Kennedy Krieger Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, USA

    Stephanie J. Mihalik, Do Kim, Paul A. Watkins & Stephen J. Gould

  2. Departments of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, USA

    Stephanie J. Mihalik & Paul A. Watkins

  3. Departments of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, USA

    James C. Morrell, Katherine A. Sacksteder & Stephen J. Gould

  4. Departments of Cell Biology and Anatomy, Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, USA

    Stephen J. Gould

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  1. Stephanie J. Mihalik
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  2. James C. Morrell
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  3. Do Kim
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  4. Katherine A. Sacksteder
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  5. Paul A. Watkins
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  6. Stephen J. Gould
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Correspondence to Stephen J. Gould.

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Mihalik, S., Morrell, J., Kim, D. et al. Identification of PAHX, a Refsum disease gene. Nat Genet 17, 185–189 (1997). https://doi.org/10.1038/ng1097-185

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