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.

Putative Prostate Cancer Risk SNP in an Androgen Receptor‐Binding Site of the Melanophilin Gene Illustrates Enrichment of Risk SNPs in Androgen Receptor Target Sites

“…The complex melanophilin/Rab27/myosin is required for the polarized transport of melanosomes along the actin cytoskeleton in melanocytes (Matesic, et al, 2001), for the pigmentation of the hair and skin (Menasche, et al, 2000) and for the secretion pathway (Fukuda, 2013). Little is known about a possible functional impact in carcinogenesis or tumor progression.…”

Macrophage activation syndrome as part of systemic juvenile idiopathic arthritis: diagnosis, genetics, pathophysiology and treatment

“…Thus, mutations in the gene encoding Rab27a, one of the MUNC13-4 effector molecules (Figure 2), have been linked to the development of Griscelli syndrome type 2. 29 Mutations in the Lyst gene have been identified as a cause of Chediak --Higashi syndrome. Both disorders can be complicated by the development of HLH.…”

Congenital and acquired neutropenia consensus guidelines on diagnosis from the Neutropenia Committee of the Marrow Failure Syndrome Group of the AIEOP (Associazione Italiana Emato‐Oncologia Pediatrica)

“…In these cases the panel reckoned appropriate to proceed to further more targeted analyses (genomic DNA mutation study for Shwachman-Diamond, mitochondrial DNA analysis for Pearson's syndrome, erythrocyte ADA and mutation search for Blackfan-Diamond syndrome) [18][19][20][21] aiming to make a firm diagnosis of these diseases (Table VII) In the case of early, severe and recurrent infections associated to decreased Ig serum levels, increased CRP and positive markers LGL syndrome Associated to hypersplenism (AEanemia, AEthrombocytopenia) Associated to sequestration in infectious foci of infections, overall suggesting an immunodeficiency, peripheral blood immunophenotype, response to vaccines including polysaccharide antigens, lymphocyte proliferation to mytogens are indicated before referring the patient to an Immunodeficiency Reference Center where study of mutations of genes involved in neutropenia associated with immunodeficiency can be addressed [22][23][24][25][26][27][28][29][30][31][32][33][34] (Table VII) …”