Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome (original) (raw)

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.

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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.

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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
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  2. Elodie Pastural
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  3. Jérôme Feldmann
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  4. Stéphanie Certain
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  5. Fügen Ersoy
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  6. Sophie Dupuis
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  7. Nico Wulffraat
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  8. Diana Bianchi
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  9. Alain Fischer
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  10. Françoise Le Deist
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  11. Geneviève de Saint Basile
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Correspondence toGeneviève de Saint Basile.

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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

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