Journal
NATURE GENETICS
Volume 25, Issue 2, Pages 173-176Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/76024
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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 transplantation(1,2). In contrast, early in life some GS patients show a severe neurological impairment without apparent immune abnormalities(3-5). We previously mapped the GS locus to chromosome 15q21 and found a mutation in a gene (MY05A) encoding a molecular motor in two patients(5). Further linkage analysis suggested a second gene associated with CS was in the same chromosomal region(6). Homozygosity mapping in additional families narrowed the candidate region to a 3.1-cM interval between D1551003 and D155962. We detected mutations in RAB27A, which lies within this interval, in 16 patients with CS. 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 MY05A 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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