Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome
Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome
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DOI：
10.1038/76024
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发表时间：
2000-06-01
期刊：
影响因子：
30.8
通讯作者：
de Saint Basile, G
中科院分区：
文献类型：
--
作者：
Ménasché, G;Pastural, E;de Saint Basile, G
Griscelli综合征（GS，MIM 214450）是一种罕见的常染色体隐性遗传病，导致皮肤和头发的色素性稀释，毛干中存在大的色素团块，黑素细胞中黑素体的积累。大多数患者还出现不受控制的T淋巴细胞和巨噬细胞活化综合征（称为噬血细胞综合征，HS），在没有骨髓移植的情况下导致死亡（1，2）。相比之下，在生命早期，一些GS患者显示出严重的神经损伤，而没有明显的免疫异常（3-5）。我们先前将GS基因定位于染色体15 q21，并在两名患者中发现编码分子马达的基因（MY 05 A）突变（5）。进一步的连锁分析表明，与CS相关的第二个基因位于同一染色体区域（6）。纯合性映射在其他家庭缩小候选区域之间的D1551003和D155962的3.1厘米的间隔。我们在16例CS患者中检测到RAB 27 A突变，该突变位于此区间内。与MYO 5A不同，GTP结合蛋白RAB 27 A似乎参与免疫系统的控制，因为所有具有RAB 27 A突变的患者，但没有MY 05 A突变的患者，都发生了HS。此外，RAB 27 A缺陷型T细胞表现出降低的细胞毒性和溶细胞颗粒胞吐作用，而MYO 5A缺陷型T细胞则没有。RAB 27 A似乎是细胞毒性颗粒胞吐作用的关键效应子，细胞毒性颗粒胞吐作用是免疫稳态所必需的途径。
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.