Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Identification and mutation analysis of the complete gene for Chediak–Higashi syndrome

Nature Genetics volume 14, pages 307–311 (1996)Cite this article

Abstract

Chediak-Higashi syndrome (CHS) is a rare, autosomal recessive disorder characterized by hypopigmentation, severe immunologic deficiency with neutropenia and lack of natural killer (NK) cells, a bleeding tendency and neurologic abnormalities1–4. Most patients die in childhood. The CHS hallmark is the occurrence of giant inclusion bodies and organelles in a variety of cell types, and protein sorting defects into these organelles5–8. Similar abnormalities occur in the beige mouse6,7,9–13, the proposed model for human CHS. Two groups have recently reported the identification of the beige gene14,15, however the two cDNAs were not at all similar. Here we describe the sequence of a human cDNA homologous to mouse beige, identify pathologic mutations and clarify the discrepancies of the previous reports. Analysis of the CHS polypeptide demonstrates that its modular architecture is similar to the yeast vacuolar sorting protein, VPS15.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Similar content being viewed by others

References

  1. Beguez-Cesar, A.B. Neutropenia cronica maligna familiar congranulaciones atipicas de los leucocitos. Bol. Soc. Cubana Pediatr. 15, 900–922 (1943).

    Google Scholar 

  2. Steinbrinck, W. Uber eine neue Granulationsanomalie der Leukocyten. Dtsch. Arch. Klin. Med. 193, 577–581 (1948).

    Google Scholar 

  3. Chediak, M. Nouvelle anomalie leukocytaire de caractere constitutionnel et familiel. Rev. Hematol. 7, 362–367 (1952).

    CAS  PubMed  Google Scholar 

  4. Higashi, O. Congenital gigantism of peroxidase granules. Tohoku J. Exp. Med. 59, 315–332 (1954).

    Article  CAS  Google Scholar 

  5. Jones, K.L., Stewart, R.M., Fowler, M., Fukuda, M. & Holcombe, R.F. Chediak-Higashi lymphoblastoid cell lines: granule characteristics and expression of lysosome-associated membrane proteins. Clin. Immunol. Immunopath. 65, 219–226 (1992).

    Article  CAS  Google Scholar 

  6. Burkhardt, J.K., Wiebel, F.A., Hester, S. & Argon, Y. The giant organelles in Beige and Chediak-Higashi fibroblasts are derived from late endosomes and mature lysosomes. J. Exp. Med. 178, 1845–1856 (1993).

    Article  CAS  Google Scholar 

  7. Holcombe, R.F., Jones, K.L. & Stewart, R.M. Lysosomal enzyme activities in Chediak-Higashi syndrome: evaluation of lymphoblastoid cell lines and review of the literature. Immunodeficiency 5, 131–140 (1994).

    CAS  Google Scholar 

  8. Zhao, H. et al. On the analysis of the pathophysiology of Chediak-Higashi syndrome. Lab. Investig. 71, 25–34 (1994).

    CAS  PubMed  Google Scholar 

  9. Lutzner, M.A., Lowrie, C.T. & Jordan, H.W. Giant granules in leukocytes of the beige mouse. Heredity 58, 299–300 (1966).

    Article  Google Scholar 

  10. Brandt, E.J., Elliott, R.W. & Swank, R.T. Defective lysosomal enzyme secretion in kidneys of Chediak-Higashi (beige) mice. J. Cell Biol. 67, 774–788 (1975).

    Article  CAS  Google Scholar 

  11. Swank, R.T. & Brandt, E.J. Turnover of kidney β-glucuronidase in normal and Chediak-Higashi (beige) mice. Am. J. Pathol. 92, 755–771 (1978).

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Willingham, M.C., Spicer, S.S. & Vincent, R.A., The origin and fate of large dense bodies in beige mouse fibroblasts. Exp. Cell Res. 136, 157–168 (1981).

    Article  CAS  Google Scholar 

  13. Penner, J.D. & Prieur, D.J. A comparative study of the lesions in cultured fibroblasts of humans and four species of animals with Chediak-Higashi syndrome. Am. J. Med. Genet. 28, 445–454 (1987).

    Article  CAS  Google Scholar 

  14. Perou, C.M. et al. Identification of the murine beige gene by YAC complementation and positional cloning. Nature Genet. 13, 303–308 (1996).

    Article  CAS  Google Scholar 

  15. Barbosa, M.D.F.S. et al. Identrtication of the homologous beige and Chediak-Higashi syndrome genes. Nature 382, 262–265 (1996).

    Article  CAS  Google Scholar 

  16. Stein, L., Kruglyak, L., Slonim, D. & Lander, E. Unpublished software, Whitehead Institute/MIT Center for Genome Research (1995).

  17. Fukai, K. et al. Homozygosity mapping of the gene for Chediak-Higashi syndrome to chromosome 1q42–q44 in a segment of conserved synteny that includes the mouse beige locus (bg). Am. J. Hum. Genet., 59, 620–624 (1996).

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Barret, F.J. et al. Genetic and physical mapping of the Chediak-Higashi syndrome on chromosome 1q42–43. Am. J. Hum. Genet. 59, 625–632 (1996).

    Google Scholar 

  19. Bork, P. & Koonin, E.V. Protein sequence motifs. Curr. Opin. Struct. Biol. 6, 366–376 (1996).

    Article  CAS  Google Scholar 

  20. Peifer, M., Berg, S. & Reynolds, A.B. A repeating amino acid motif shared by proteins with diverse cellular roles. Cell 76, 789–791 (1994).

    Article  CAS  Google Scholar 

  21. Andrade, M.A. & Bork, P. HEAT repeats in the Huntington's disease protein. Nature Genet. 11, 115–116 (1995).

    Article  CAS  Google Scholar 

  22. DiFiglia, M. et al. Huntingtin is a cytoplasmic protein associated with vesicles in human and rat brain neurons. Neuron 14, 1075–1081 (1995).

    Article  CAS  Google Scholar 

  23. Sabatini, D.M., Erdjument-Bromage, H., Lui, M., Tempst, P. & Snyder, S.H. RAFT1: a mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell 78, 35–43 (1994).

    Article  CAS  Google Scholar 

  24. Zheng, X.F., Florentine, D., Chen, J., Crabtree, G.R. & Schreiber, S.L. TOR kinase domains are required for two distinct functions, only one of which is inhibited by rapamycin. Cell 82, 121–130 (1995).

    Article  CAS  Google Scholar 

  25. Hemmings, B.A. et al. α-and β-forms of the 65-kDa subunit of protein phosphatase 2A have a similar 39 amino acid repeating structure. Biochemistry 29, 3166–3173 (1990).

    Article  CAS  Google Scholar 

  26. 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).

    Article  CAS  Google Scholar 

  27. Sondek, J., Bohm, A., Lambright, D.G., Hamm, H.E. & Sigler, P.B. Crystal structure of a GA protein beta gamma dimer at 2.1A resolution. Nature 379, 369–374 (1996).

    Article  CAS  Google Scholar 

  28. Wall, M.A. et al. The structure of the G protein heterotrimer Gi α1β1γ2. 83, 1047–1058 (1995).

  29. Belmont, L.D. & Mitchison, T.J. Identification of a protein that interacts with tubulin dimers and increases the catastrophe rate of microtubules. Cell 84, 623–631 (1996).

    Article  CAS  Google Scholar 

  30. Lupas, A.N. et al. Predicting coiled coils from protein sequences. Science 252, 1162–1164 (1991).

    Article  CAS  Google Scholar 

  31. Klionsky, D.J. & Emr, S.D. A new class of lysosomal/vacuolar protein sorting signals. J. Biol. Chem. 265, 5349–5352 (1990).

    CAS  PubMed  Google Scholar 

  32. Herman, P.K., Stack, J.H. & Emr, S.D. A genetic and structural analysis of the yeast Vps15 protein kinase: evidence for a direct role of VPS15p in vacuolar protein delivery. EMBO J. 10, 4049–60 (1991).

    Article  CAS  Google Scholar 

  33. Stack, J.H., Herman, P.K., Schu, P.V. & Emr, S.D. A membrane-associated complex containing the Vps15 protein kinase and the VPS34 PI 3-kinase is essential for protein sorting to the yeast lysosome-like vacuole. EMBO J. 12, 2195–204 (1993).

    Article  CAS  Google Scholar 

  34. 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  Google Scholar 

  35. Altschul, S.F., Boguski, M.S., Gish, W. & Wootton, J.C. Issues in searching molecular sequence databases. Nature Genet. 6, 119–129 (1994).

    Article  CAS  Google Scholar 

  36. Wootton, J.C. & Federhen, S. Analysis of compositionally biased regions in sequence databases. Meth. Enz. 266, 554–571 (1996).

    Article  CAS  Google Scholar 

  37. Rost, B., Sander, C. & Schneider, R. PHD—an automatic mail server for protein secondary structure prediction. Comput. Appl. Biosci. 10, 53–60 (1994).

    CAS  PubMed  Google Scholar 

  38. Bork, P. & Gibson, T. Applying motif and profile searches. Meth. Enz. 266, 162–184 (1996).

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Millennium Pharmaceuticals, Inc., 640 Memorial Dr., Cambridge, Massachusetts, 02139, USA

    Deborah L. Nagle, Elizabeth A. Woolf, Lisa Holmgren, Donald J. Misumi, Sonja H. McGrail, Barry J. Dussault Jr., Geoffrey M. Duyk & Karen J. Moore

  2. Departments of Medical Genetics and Pediatrics, University of Wisconsin, Madison, Wisconsin, 53706, USA

    Mohammad A. Karim & Richard A. Spritz

  3. European Molecular Biology Laboratories, Heidelberg

    Peer Bork

  4. Division of Cell Biology and Immunology, Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah, 84132, USA

    Charles M. Perou

  5. Department of Dermatology, University of Cincinnati College of Medicine, Cincinnati, Ohio, 45267, USA

    Raymond E. Boissy

  6. Max-DelbrüCentre for Molecular Medicine, Berlin-Buch, Germany

    Peer Bork

Authors
  1. Deborah L. Nagle
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mohammad A. Karim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Elizabeth A. Woolf
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Lisa Holmgren
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Peer Bork
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Donald J. Misumi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sonja H. McGrail
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Barry J. Dussault Jr.
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Charles M. Perou
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Raymond E. Boissy
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Geoffrey M. Duyk
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Richard A. Spritz
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Karen J. Moore
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nagle, D., Karim, M., Woolf, E. et al. Identification and mutation analysis of the complete gene for Chediak–Higashi syndrome. Nat Genet 14, 307–311 (1996). https://doi.org/10.1038/ng1196-307

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng1196-307

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing