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:

Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome

Nature Genetics volume 25, pages 173–176 (2000)Cite this article

Abstract

Griscelli syndrome (GS, MIM 214450), a rare, autosomal recessive disorder, results in pigmentary dilution of the skin and the hair, the presence of large clumps of pigment in hair shafts and an accumulation of melanosomes in melanocytes. Most patients also develop an uncontrolled T-lymphocyte and macrophage activation syndrome (known as haemophagocytic syndrome, HS), leading to death in the absence of bone-marrow transplantation1,2. In contrast, early in life some GS patients show a severe neurological impairment without apparent immune abnormalities3,4,5. We previously mapped the GS locus to chromosome 15q21 and found a mutation in a gene (MYO5A) encoding a molecular motor in two patients5. Further linkage analysis suggested a second gene associated with GS was in the same chromosomal region6. Homozygosity mapping in additional families narrowed the candidate region to a 3.1-cM interval between D15S1003 and D15S962. We detected mutations in RAB27A, which lies within this interval, in 16 patients with GS. Unlike MYO5A, the GTP-binding protein RAB27A appears to be involved in the control of the immune system, as all patients with RAB27A mutations, but none with the MYO5A mutation, developed HS. In addition, RAB27A-deficient T cells exhibited reduced cytotoxicity and cytolytic granule exocytosis, whereas MYO5A-defective T cells did not. RAB27A appears to be a key effector of cytotoxic granule exocytosis, a pathway essential for immune homeostasis.

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

Figure 1: Genetic and physical maps of the region encompassing the GS loci on chromosome 15q21.
Figure 2: Scheme depicting the RAB27A protein and the mutations identified in patients with GS.
Figure 3: Absence of RAB27A from the P1 B cell line.
Figure 4: Defective cytotoxic activity of T lymphocytes from patients with RAB27A mutations (P1, P7, P17 and P18), but not of those from patients with MYO5A mutations (P3 and P8).
Figure 5: Defective granule release of T lymphocytes from patients with RAB27A mutations.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Griscelli, C. et al. A syndrome associating partial albinism and immunodeficiency. Am. J. Med. 65, 691–702 (1978).

    Article  CAS  Google Scholar 

  2. Klein, C. et al. Partial albinism with immunodeficiency (Griscelli syndrome). J. Pediatr. 125, 886–895 (1994).

    Article  CAS  Google Scholar 

  3. Hurvitz, H., Gillis, R., Klaus, S., Gross-Kieselstein, F. & Okon, E. A kindred with Griscelli disease: spectrum of neurological involvment. Eur. J. Pediatr. 152, 402–405 (1993).

    Article  CAS  Google Scholar 

  4. Elejalde, B.R. et al. Mutations affecting pigmentation in man: I. neuroectodermal melanolysosomal disease. Am. J. Med. Genet. 3, 65–80 (1979).

    Article  CAS  Google Scholar 

  5. Pastural, E. et al. Griscelli disease maps to chromosome 15q21 and is associated with mutations in the myosin-Va gene. Nature Genet. 16, 289–292 (1997).

    Article  CAS  Google Scholar 

  6. Pastural, E. et al. Two genes are responsible for Griscelli syndrome at the same 15q21 locus. Genomics, 63, 299–306 (2000).

    Article  CAS  Google Scholar 

  7. Tolmachova, T. et al. Cloning, mapping and characterization of the human RAB27A gene. Gene 239, 109–116 (1999).

    Article  CAS  Google Scholar 

  8. Chen, D., Guo, J., Miki, T., Tachibana, M. & Gahl, W. Molecular cloning and characterization of Rab27a and Rab27b, novel human rab proteins shared by melanocytes and platelets. Biochem. Mol. Med. 60, 27–37 (1997).

    Article  CAS  Google Scholar 

  9. Pfeffer, S.R. Rab GTPases: master regulators of membrane trafficking. Curr. Opin. Cell Biol. 6, 522–526 (1994).

    Article  CAS  Google Scholar 

  10. Novick, P. & Zerial, M. The diversity of Rab proteins in vesicle transport. Curr. Opin. Cell Biol. 9, 496–504 (1997).

    Article  CAS  Google Scholar 

  11. Kinsella, B. & Maltese, W. rab GTP-binding proteins with three different carboxyl-terminal cysteine motifs are modified in vivo by 20-carbon isoprenoids. J. Biol. Chem. 267, 3940–3945 (1992).

    CAS  PubMed  Google Scholar 

  12. Chavrier, P. & Goud, B. The role of ARF and Rab GTPases in membrane transport. Curr. Opin. Cell Biol. 11, 466–475 (1999).

    Article  CAS  Google Scholar 

  13. Stepp, S. et al. Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science 286, 1957–1959 (1999).

    Article  CAS  Google Scholar 

  14. Barrat, F.J. et al. Defective CTLA-4 cycling pathway in Chediak-Higashi syndrome: a possible mechanism for deregulation of T lymphocyte activation. Proc. Natl Acad. Sci. USA 96, 8645–8650 (1999).

    Article  CAS  Google Scholar 

  15. Cheney, R.E. et al. Brain myosin-V is a two-headed unconventional myosin with motor activity. Cell 75, 13–23 (1993).

    Article  CAS  Google Scholar 

  16. Espreafico, E.M. et al. Primary structure and cellular localization of chicken brain myosin-V (p190), an unconventional myosin with calmodulin light chains. J. Cell Biol. 119, 1541–1557 (1992).

    Article  CAS  Google Scholar 

  17. Prekeris, R. & Terrian, D.M. Brain myosin V is a synaptic vesicle-associated motor protein: evidence for a Ca2+-dependent interaction with the synaptobrevin-synaptophysin complex. J. Cell Biol. 137, 1589–1601 (1997).

    Article  CAS  Google Scholar 

  18. Echard, A. et al. Interaction of a Golgi-associated kinesin-like protein with Rab6. Science 279, 580–585 (1998).

    Article  CAS  Google Scholar 

  19. Seabra, M.C., Ho, Y.K. & Anant, J.S. Deficient geranylgeranylation of Ram/Rab27 in choroideremia. J. Biol. Chem. 270, 24420–24427 (1995).

    Article  CAS  Google Scholar 

  20. Stinchcombe, J.C. & Griffiths, G.M. Regulated secretion from hemopoietic cells. J. Cell Biol. 147, 1–5 (1999).

    Article  CAS  Google Scholar 

  21. Dufourcq-Lagelouse, R. et al. Genetic basis of hemophagocytic lymphohistiocytosis syndrome. Int. J. Mol. Med. 4, 127–133 (1999).

    CAS  PubMed  Google Scholar 

  22. Mazerolles, F. & Fischer, A. Binding of CD4 ligands induces tyrosine phosphorylation of phosphatidinylinositol-3 kinase p110 subunit. Int. Immunol. 10, 1897–1905 (1998).

    Article  CAS  Google Scholar 

  23. Kim, S. & Yokoyama, W.M. NK cell granule exocytosis and cytokine production inhibited by Ly-49A engagement. Cell. Immunol. 183, 10–112 (1998).

    Article  Google Scholar 

Download references

Acknowledgements

We thank the patients and their families for participation; referring physicians; and C. Harré and N. Lambert for technical assistance. This work was supported by grants from INSERM, l'Association Française contre les Myopathies, l'Association de Recherche contre le Cancer and the BIOMED 2 Concerted Action PL 963007.

Author information

Author notes

  1. Gaël Ménasché and Elodie Pastural: These authors contributed equally to this work.

Authors and Affiliations

  1. Unité de Recherches sur le Dévelopment Normal et Pathologique du Système Immunitaire INSERM U429, Paris, France

    Gaël Ménasché, Elodie Pastural, Jérôme Feldmann, Stéphanie Certain, Alain Fischer, Françoise Le Deist & Geneviève de Saint Basile

  2. University of Hacettepe, Pediatric Immunology Unit, Hacettepe Children's Hospital, Ankara, Turkey

    Fügen Ersoy

  3. Unité d'Immunologie et d'Hématologie Pédiatrique, Hôpital Necker-Enfants Malades, Paris, France

    Sophie Dupuis, Alain Fischer & Françoise Le Deist

  4. Pediatric Immunology, KC03.63.0, Wilhelmina Children's Hospital, Utrecht, The Netherlands

    Nico Wulffraat

  5. New England Medical Center, Boston, Massachusetts, USA

    Diana Bianchi

Authors
  1. Gaël Ménasché
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Elodie Pastural
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jérôme Feldmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Stéphanie Certain
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Fügen Ersoy
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sophie Dupuis
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Nico Wulffraat
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Diana Bianchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Alain Fischer
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Françoise Le Deist
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Geneviève de Saint Basile
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Geneviève de Saint Basile.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ménasché, G., Pastural, E., Feldmann, J. et al. Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome. Nat Genet 25, 173–176 (2000). https://doi.org/10.1038/76024

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/76024

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