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Hermansky-Pudlak syndrome is caused by mutations in HPS4, the human homolog of the mouse light-ear gene

Nature Genetics volume 30, pages 321–324 (2002)Cite this article

Abstract

Hermansky-Pudlak syndrome (HPS) is a disorder of organelle biogenesis in which oculocutaneous albinism, bleeding and pulmonary fibrosis result from defects of melanosomes, platelet dense granules and lysosomes1,2,3,4. HPS is common in Puerto Rico5,6, where it is caused by mutations in the genes HPS17 and, less often, HPS3 (ref. 8). In contrast, only half of non–Puerto Rican individuals with HPS have mutations in HPS1 (ref. 9), and very few in HPS3 (ref. 10). In the mouse, more than 15 loci manifest mutant phenotypes similar to human HPS11,12, including pale ear (ep), the mouse homolog of HPS1 (refs 13,14). Mouse ep has a phenotype identical to another mutant, light ear (le)15,16,17,18, which suggests that the human homolog of le is a possible human HPS locus. We have identified and found mutations of the human le homolog, HPS4, in a number of non–Puerto Rican individuals with HPS, establishing HPS4 as an important HPS locus in humans. In addition to their identical phenotypes, le and ep mutant mice have identical abnormalities of melanosomes, and in transfected melanoma cells the HPS4 and HPS1 proteins partially co-localize in vesicles of the cell body. In addition, the HPS1 protein is absent in tissues of le mutant mice. These results suggest that the HPS4 and HPS1 proteins may function in the same pathway of organelle biogenesis.

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Figure 1: Comparison of wildtype (C57BL/6J), pale-ear mutant (ep/ep) and light-ear mutant (le/le) mice.
Figure 2: Alignment of the mouse HPS4 polypeptide sequence with homologous segments translated from human, cow, pig, rat, chick, frog, Medaka fish and Drosophila.
Figure 3: Defects of melanosome number and structure in retina of C57BL/6J-le/le and C57BL/6J-+/+ mice.
Figure 4: Immunoblot analysis of HPS1 in platelets from light-ear mutant mice.
Figure 5: Expression of mouse FLAG-HPS4 protein in transfected human MNT-1 melanoma cells.

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References

  1. Hermansky, F. & Pudlak, P. Albinism associated with hemorrhagic diathesis and unusual pigmented reticular cells in the bone marrow. Blood 14, 162–169 (1959).

    CAS  PubMed  Google Scholar 

  2. Spritz, R.A. Multi-organellar disorders of pigmentation: tied up in traffic. Clin. Genet. 55, 309–317 (1999).

    Article  CAS  Google Scholar 

  3. Spritz, R.A. Multi-organellar disorders of pigmentation: intracellular traffic jams in mammals, flies, and yeast. Trends Genet. 15, 337–340 (1999).

    Article  CAS  Google Scholar 

  4. Spritz, R.A. Hermansky-Pudlak syndrome and pale ear: melanosome-making for the millennium. Pig. Cell. Res. 13, 15–20 (2000).

    Article  CAS  Google Scholar 

  5. Witkop, C.J., Almadovar, C., Pineiro, B. & Babcock, M.N. Hermansky-Pudlak syndrome (HPS). An epidemiologic study. Ophth. Paediatr. Genet. 11, 245–250 (1990).

    Article  CAS  Google Scholar 

  6. Witkop, C.J. et al. Albinism and Hermansky-Pudlak syndrome in Puerto Rico. Bol. Assoc. Med. P. R. 82, 333–339 (1990).

    CAS  Google Scholar 

  7. Oh, J. et al. Positional cloning of a gene for Hermansky-Pudlak syndrome, a disorder of cytoplasmic organelles. Nature Genet. 14, 300–306 (1996).

    Article  CAS  Google Scholar 

  8. Anikster, Y. et al. Mutation of a new gene causes a unique form of Hermansky-Pudlak syndrome in a genetic isolate of central Puerto Rico. Nature Genet. 28, 376–380 (2001).

    Article  CAS  Google Scholar 

  9. Oh, J. et al. Mutation analysis of patients with Hermansky-Pudlak syndrome defines a frameshift hotspot in the HPS gene as well as apparent locus heterogeneity. Am. J. Hum. Genet. 62, 593–598 (1998).

    Article  CAS  Google Scholar 

  10. Suzuki, T. et al. The gene mutated in cocoa mice, carrying a defect of organelle biogenesis, is a homologue of the human Hermansky-Pudlak Syndrome-3 gene. Genomics 78, 1–8 (2001).

    Article  Google Scholar 

  11. Bennett, D. Genetics, development, and malignancy of melanocytes. Int. Rev. Cytol. 146, 191–260 (1993).

    Article  CAS  Google Scholar 

  12. Swank, R.T., Novak, E.K., McGarry, M.P., Rusiniak, M.E. & Feng, L. Mouse models of Hermansky-Pudlak syndrome: a review. Pig. Cell. Res. 11, 60–80 (1998).

    Article  CAS  Google Scholar 

  13. Feng, G.H., Bailin, T., Oh, J. & Spritz, R.A. Mouse pale ear (ep) is homologous to human Hermansky-Pudlak syndrome and contains a rare “AT-AC” intron. Hum. Mol. Genet. 6, 793–797 (1997).

    Article  CAS  Google Scholar 

  14. Gardner, J.M. et al. The mouse pale ear (ep) mutation is the homologue of human Hermansky Pudlak syndrome (HPS). Proc. Natl Acad. Sci. USA 94, 9238–9243 (1997).

    Article  CAS  Google Scholar 

  15. Lane, P.W. Linkage groups 3 and XVII in the mouse and the position of the light-ear locus. J. Hered. 58, 21–24 (1967).

    Article  CAS  Google Scholar 

  16. Lane, P.W. & Green, E.L. Pale ear and light ear in the house mouse: mimic mutations in linkage groups XII and XVII. J. Hered. 58, 17–20 (1967).

    Article  CAS  Google Scholar 

  17. Meisler, M., Levy, J., Sansone, F. & Gordon, M. Morphologic and biochemical abnormalities of kidney lysosomes in mice with an inherited albinism. Am. J. Pathol. 101, 581–594 (1980).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Novak, E.K., Hui, S.-W. & Swank, R.T. Platelet storage pool deficiency in mouse pigment mutations associated with seven distinct genetic loci. Blood 63, 536–544 (1984).

    CAS  PubMed  Google Scholar 

  19. Meisler, M.H., Wanner, L. & Strahler, J. Pigmentation and lysosomal phenotypes in mice doubly homozygous for both light-ear and pale-ear mutant alleles. J. Hered. 75, 103–106 (1984).

    Article  CAS  Google Scholar 

  20. Chapman, V.M., Noell, W.K. & Adler, D. Alb-1. Mouse News Lett. 53, 61 (1975).

    Google Scholar 

  21. Buckler, A.J. et al. Exon amplification: a strategy to isolate mammalian genes based on RNA splicing. Proc. Natl Acad. Sci. USA 88, 4005–4009 (1991).

    Article  CAS  Google Scholar 

  22. Altschul, S.F. et al. Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res. 25, 3389–3402 (1997).

    Article  CAS  Google Scholar 

  23. Dunham, I. et al. The DNA sequence of human chromosome 22. Nature 402, 489–495 (1999).

    Article  CAS  Google Scholar 

  24. Lee, S.-T., Park, S.-K., Lee, K.-H., Holmes, S.A. & Spritz, R.A. A non-radioactive method for simultaneous detection of single-strand conformation polymorphisms (SSCPs) and heteroduplexes. Molecules Cells 5, 668–672 (1995).

    CAS  Google Scholar 

  25. Spritz, R.A. Chediak-Higashi syndrome. in Primary Immunodeficiency Diseases (eds Ochs, H.D., Smith, C.I.E. & Puck, J.M.) 389–396 (Oxford University Press, New York, 1999).

    Google Scholar 

  26. Feng, L. et al. The β3A subunit gene (Ap3b1) of the AP-3 adaptor complex is altered in the mouse hypopigmentation mutant pearl, a model for Hermansky-Pudlak syndrome and night blindness. Hum. Mol. Genet. 8, 323–330 (1999).

    Article  CAS  Google Scholar 

  27. Dell'Angelica, E.C., Shotelersuk, V., Aguilar, R.C., Gahl, W.A. & Bonifacino, J.S. Altered trafficking of lysosomal proteins in Hermansky-Pudlak syndrome due to mutations in the b3A subunit of the AP-3 adaptor. Mol. Cell 3, 1–20 (1999).

    Article  Google Scholar 

  28. Oh, J., Liu, Z.-X., Feng, G.H., Raposo, G. & Spritz, R.A. The Hermansky-Pudlak syndrome (HPS) protein is part of a high molecular weight complex involved in biogenesis of early melanosomes. Hum. Mol. Genet. 9, 375–385 (2000).

    Article  CAS  Google Scholar 

  29. Cuomo, M. et al. Production and characterization of the murine monoclonal antibody 2G10 to a human T4-tyrosinase epitope. J. Invest. Dermatol. 96, 446–451 (1991).

    Article  CAS  Google Scholar 

  30. Robinson, M.S. & Bonifacino, J.S. Adaptor-related proteins. Curr. Opin. Cell Biol. 13, 444–453 (2001).

    Article  CAS  Google Scholar 

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Acknowledgements

This work was supported by grants from the National Insitutes of Health (to R.A.S, R.T.S. and the Roswell Park Cancer Institute) and the Wellcome Trust (to E.V.S.). We thank A. Wilson, Y. Jiang, L. Zhen, D. Tabaczynski, D. Poslinski and M.K. Ellsworth for technical assistance.

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Authors and Affiliations

  1. Human Medical Genetics Program, University of Colorado Health Sciences Center, Denver, 80262, Colorado, USA

    Tamio Suzuki & Richard A. Spritz

  2. Department of Molecular and Cellular Biology, Roswell Park Cancer Institute, Buffalo, New York, USA

    Wei Li, Qing Zhang, Amna Karim, Edward K. Novak & Richard T. Swank

  3. Department of Anatomy and Cell Biology, St. George's Hospital Medical School, London, UK

    Elena V. Sviderskaya, Simon P. Hill & Dorothy C. Bennett

  4. Departments of Ophthalmology, Pediatrics, and Genetics, Hospital for Sick Children, Toronto, Ontario, Canada

    Alex V. Levin

  5. Department of Hematology, University Hospital Utrecht, Utrecht, The Netherlands

    H. Karel Nieuwenhuis

  6. Department of Pediatrics, University of Rochester Medical Center, Rochester, New York, USA

    Chin-To Fong

  7. Genetische Beratungsstelle, Bolzano, Italy

    Claudio Castellan

  8. Abteilung für Molekulare Humangenetik, Ruhr-Universität Bochum, Bochum, Germany

    Bianca Miterski

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Correspondence to Richard A. Spritz.

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Suzuki, T., Li, W., Zhang, Q. et al. Hermansky-Pudlak syndrome is caused by mutations in HPS4, the human homolog of the mouse light-ear gene. Nat Genet 30, 321–324 (2002). https://doi.org/10.1038/ng835

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