Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome


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.

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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.

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  1. 1

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

  2. 2

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

  3. 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).

  4. 4

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

  5. 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).

  6. 6

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

  7. 7

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

  8. 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).

  9. 9

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

  10. 10

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

  11. 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).

  12. 12

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

  13. 13

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

  14. 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).

  15. 15

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

  16. 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).

  17. 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).

  18. 18

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

  19. 19

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

  20. 20

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

  21. 21

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

  22. 22

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

  23. 23

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

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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.

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Correspondence to Geneviève de Saint Basile.

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