title: Mutations in RAB27A cause Griscelli syndrome associated with haemophagocytic syndrome.
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 transplantation. In contrast, early in life some GS patients show a severe neurological impairment without apparent immune abnormalities. We previously mapped the GS locus to chromosome 15q21 and found a mutation in a gene (MYO5A) encoding a molecular motor in two patients. Further linkage analysis suggested a second gene associated with GS was in the same chromosomal region. 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.
authors.affiliation: [1] Unité de Recherches sur le Dévelopment Normal et Pathologique du Système Immunitaire INSERM U429, Paris, France.
authors.forename: G
authors.initials: G
authors.lastname: Ménasché
authors.forename: E
authors.initials: E
authors.lastname: Pastural
authors.forename: J
authors.initials: J
authors.lastname: Feldmann
authors.forename: S
authors.initials: S
authors.lastname: Certain
authors.forename: F
authors.initials: F
authors.lastname: Ersoy
authors.forename: S
authors.initials: S
authors.lastname: Dupuis
authors.forename: N
authors.initials: N
authors.lastname: Wulffraat
authors.forename: D
authors.initials: D
authors.lastname: Bianchi
authors.forename: A
authors.initials: A
authors.lastname: Fischer
authors.forename: F
authors.initials: F
authors.lastname: Le Deist
authors.forename: G
authors.initials: G
authors.lastname: de Saint Basile
mesh_terms: D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics; D003594:Cytoplasmic Granules / Q000378:metabolism; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005260:Female; D005656:Fungal Proteins / Q000235:genetics; D008040:Genetic Linkage / Q000235:genetics; D006720:Homozygote; D006801:Humans; D007223:Infant; D007438:Introns / Q000235:genetics; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D024461:Myosin Type I; D009218:Myosins / Q000235:genetics; D010859:Pigmentation Disorders / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D029701:Saccharomyces cerevisiae Proteins; D013577:Syndrome; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology / Q000378:metabolism; D020691:rab GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D000075745:rab27 GTP-Binding Proteins
chemical_list: D005656:Fungal Proteins; C100412:MYO5 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D000075745:rab27 GTP-Binding Proteins; D024461:Myosin Type I; C066694:RAB27A protein, human; D009218:Myosins; D020691:rab GTP-Binding Proteins