Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome

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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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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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