A novel missense mutation (G43S) in the switch I region of Rab27A causing Griscelli syndrome

Abstract

The autosomal recessive Griscelli syndrome type II (GSII) is caused by mutations in the RAB27A gene. Typical clinical features include immunological impairment, silver-gray scalp hair, eyelashes and eyebrows, and hypomelanosis of the skin. Rabs help determine the specificity of membrane trafficking steps within cells. In melanocytes, the GTP-bound form of Rab27A associates with the membranes of mature fully-pigmented melanosomes through its geranylgeranyl group. Once attached, Rab27A recruits the downstream effector Melanophilin (Mlph) and the actin-dependent motor protein Myosin Va (MyoVa). The molecular Rab27A/Mlph/MyoVA tripartite complex, which links melanosomes to the peripheral actin network, is required to achieve melanosome transfer to surrounding keratinocytes in the epidermis. Here we report a novel homozygous missense mutation c.127G>A, p.G43S in exon 2 of the RAB27A gene of an Afghani GSII patient. Laser scanning confocal microscopy showed that the G43S mutation, which is located in the highly conserved switch I region of Rab27A, induces perinuclear localization of melanosomes in normal melanocytes, and fails to restore melanosomes to the actin-rich periphery in GSII melanocytes. Coimmunoprecipitation studies showed that Rab27A(G43S) fails to interact with its effector Melanophilin, indicating that the Switch I region functions in the recruitment of Rab effector proteins.

Overexpression of Rab27B is correlated with distant metastasis and poor prognosis in ovarian cancer

“…The majority of Rab proteins perform identical basic functions in all cells, whereas others are only observed in certain cell types, where they perform specialized functions. The Rab27 subfamily members, which include the homologues Rab27A and B, are 71% identical at the amino acid level and have been detected in several secretory tissues and hematopoietic cells (17)(18)(19). Rab27B may enhance proliferation under limiting serum concentrations, via increased G1-S-phase cell cycle transition.…”

Hematopoietic stem cell transplantation in Griscelli syndrome type 2: a single-center report on 10 patients

“…Ideally, bone marrow transplantation in GS2 patients should be performed before the first episode of HLH. 12,17 Primary engraftment failure occurred in one patient (who was not in complete remission from HLH at time of transplantation). This fits with previous reports of HSCT failure in patients with active HLH at the time of HSCT 29,31,42 and could be explained by a negative effect of circulating cytokines during the active disease phase; for example, interferon-␥ (IFN-␥) has been shown to have a negative effect on hematopoiesis in murine models.…”

“…12 Few cases of successful HSCT from compatible donors have been reported in children with GS2 thereafter. [13][14][15][16][17] A recent study emphasizes the neurologic sequelae in 5 of 5 GS2 patients who received HSCT after treatment according to the HLH-94/HLH-2004 protocol. 18 The present study shows and discusses the results and complications of HSCT performed in 10 GS2 patients in a single center between 1996 and 2008. neurologic involvement and another additional patient's family refused HSCT.…”

The secretory small GTPase Rab27B as a marker for breast cancer progression

“…Specificity of the rabbit polyclonal Rab27B antibody has been shown previously [3,11]. Evaluation of the specific goat polyclonal Rab27A antibody for laser scanning confocal microscopy was performed on primary human melanocytes, a cell type with a well studied expression and localization pattern of Rab27A [10,16] (Fig. 2B).…”

“…Secretory Rab GTPases control regulated vesicle exocytosis [6]. After cloning the secretory Rab27A and Rab27B genes [7], our group has continued to study the cellular function of this Rab subfamily [3,[8][9][10]. The secretory Rab27 subfamily consists of the homologues Rab27A and B; they exhibit 71% identity at the amino acid level.…”