Abstract
VESICULAR transport to and from the lysosome and late endosome is defective in patients with Chediak–Higashi syndrome (CHS) and in mutant beige (bg) mice1–4. CHS and bg cells have giant, perinuclear vesicles with characterises of late endosomes and lysosomes that arise from dysregulated homotypic fusion3–5. CHS and bg lysosomes also exhibit compartmental missorting of proteins, such as elastase, glucuronidase and cathepsin G2,3,6,7. Lyst, a candidate gene for bg, was identified by direct complementary DNA selection from a yeast artificial chromosome (YAC) clone containing a 650-kilobase segment of the bg-critical region on mouse chromosome 13. Lyst is disrupted by a 5-kilobase deletion in bg11J mice, and Lyst messenger RNA is markedly reduced in bg2J homozygotes. The homologous human gene, LYST, is highly conserved with mouse Lyst, and contains a frame-shift mutation at nucleotides 117–118 of the coding domain in a CHS patient. Thus bg mice and human CHS patients have homologous disorders associated with Lyst mutations. Lyst encodes a protein with a carboxy-terminal prenylation motif and multiple potential phosphorylation sites. Lyst protein is predicted to form extended helical domains, and has a region of sequence similar to stathmin, a coiled-coil phosphoprotein thought to act as a relay integrating cellular signal response coupling8–10.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Blume, R. S. & Wolff, S. M. Med. Baltimore 51, 247–280 (1972).
Zhao, H. et al. Lab. Invest. 71, 25–34 (1994).
Brandt, E. J., Elliott, R. W. & Swank, R. T. J. Cell Biol. 67, 774–788 (1975).
Burkhardt, J. K., Wiebel, F. A., Hester, S. & Argon, Y. J. exp. Med. 178, 1845–1856 (1993).
Willingham, M. C., Spicer, S. S. & Vincent, R. A. Expl Cell Res. 136, 157–168 (1981).
Holcombe, R. F., Jones, K. L. & Stewart, R. M. Immunodeficiency 5, 131–140 (1994).
Swank, R. T. & Brandt, E. J. Am. J. Path. 92, 755–769 (1978).
Sobel, A. Trends biochem. Sci. 16, 301–305 (1991).
Maucuer, A., Camonis, J. H. & Sobel, A. Proc. natn. Acad. Sci. U.S.A. 92, 3100–3104 (1995).
Belmont, L. D. & Mitchison, T. J. Cell 84, 623–631 (1996).
Barbosa, M. D. F. S. et al. Genomics 30, 439–444 (1995).
Kingsmore, S. F. et al. J. invest. Med. (in the press).
Kingsmore, S. F. et al. Mamm. Genome (in the press).
Kingsmore, S. F. et al. Nature Genet. 7, 136–142 (1994).
Perou, C. M. & Kaplan, J. Somat. Cell molec. Genet. 19, 459–468 (1993).
Oliver, J. M., Zurier, R. B. & Berlin, R. D. Nature 253, 471–473 (1975).
Oliver, J. M. & Zurier, R. B. J. clin. Invest. 57, 1239–1247 (1976).
Clarke, S. A. Rev. Biochem. 61, 355–386.
Sato, A. et al. J. Leuk. Biol. 48, 377–381 (1990).
Ito, M. et al. Biochem. biophys. Res. Commun. 160, 433 (1989).
Gallin, J. I., Bujak, J. S., Patten, E. & Sheldon, M. W. Blood 43, 201–206 (1974).
Roder, J. & Duwe, A. Nature 278, 451–453 (1979).
Saxena, R. K., Saxena, Q. B. & Adler, W. H. Nature 295, 240–241 (1982).
Baetz, K., Isaaz, S. & Griffiths, M. J. Immun. 154, 6122–6131 (1995).
Kusumi, K. et al. Mamm. Genome 4, 391–392 (1993).
Pierce, J. C., Sauer, B. & Sternberg, N. Proc. natn. Acad. Sci. U.S.A. 89, 2056–2060 (1992).
Gribrat, J. F., Garnier, J. & Robson, B. J. molec. Biol. 198, 425–443 (1987).
Deleage, G. & Roux, B. Protein Engng 1, 289–294 (1987).
Geourjon, C. & Deleage, G. Protein Engng 7, 157–164 (1994).
Rost, B. & Sander, C. Proteins 19, 55–72 (1994).
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Barbosa, M., Nguyen, Q., Tchernev, V. et al. Identification of the homologous beige and Chediak–Higashi syndrome genes. Nature 382, 262–265 (1996). https://doi.org/10.1038/382262a0
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/382262a0
This article is cited by
-
LYST deficiency impairs autophagic lysosome reformation in neurons and alters lysosome number and size
Cellular and Molecular Life Sciences (2023)
-
Assisted reproduction mediated resurrection of a feline model for Chediak-Higashi syndrome caused by a large duplication in LYST
Scientific Reports (2020)
-
Mouse models and strain-dependency of Chédiak-Higashi syndrome-associated neurologic dysfunction
Scientific Reports (2019)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.