Abstract
Griscelli syndrome type 2 (GS-2) is an inborn error of immunity characterized by partial albinism and episodes of hemophagocytic lymphohistiocytosis (HLH). It is caused by RAB27A mutations that encode RAB27A, a member of the Rab GTPase family. RAB27A is expressed in many tissues and regulates vesicular transport and organelle dynamics. Occasionally, GS-2 patients with RAB27A mutation display normal pigmentation. The study of such variants provides the opportunity to map distinct binding sites for tissue-specific effectors on RAB27A. Here we present a new case of GS-2 without albinism (GS-2 sine albinism) caused by a novel missense mutation (Val143Ala) in the RAB27A and characterize its functional cellular consequences. Using pertinent animal cell lines, the Val143Ala mutation impairs both the RAB27A–SLP2-A interaction and RAB27A–MUNC13-4 interaction, but it does not affect the RAB27A–melanophilin (MLPH)/SLAC2-A interaction that is crucial for skin and hair pigmentation. We conclude that disruption of the RAB27A–MUNC13-4 interaction in cytotoxic lymphocytes leads to the HLH predisposition of the GS-2 patient with the Val143Ala mutation. Finally, we include a review of GS-2 sine albinism cases reported in the literature, summarizing their genetic and clinical characteristics.
Highlights
Griscelli syndrome type 2 (GS-2; MIM#607624) is an inborn error of immunity (IEI) characterized by partial albinism and the occurrence of acute phases of hemophagocytic lymphohistiocytosis (HLH) [1, 2]
The results showed that the Val143Ala mutation dramatically reduced the binding activity toward MUNC13-4 and SLP2-A (Figures 5A, B)
Because RAB27A is known to regulate actin-based melanosome transport in melanocytes and lytic granule exocytosis in cytotoxic T lymphocytes through interaction with cell-type-specific or tissuespecific effectors [33], we investigated the effect of the Val143Ala mutation of RAB27A on binding activity toward its effectors
Summary
Griscelli syndrome type 2 (GS-2; MIM#607624) is an inborn error of immunity (IEI) characterized by partial albinism and the occurrence of acute phases of hemophagocytic lymphohistiocytosis (HLH) [1, 2]. RAB27A (MIM *603868) gene mutations are responsible for GS-2. RAB27A is highly expressed in melanocytes and a variety of secretory cells, including lymphocytes [5]. RAB27A effector/melanophilin (MLPH, known as SLAC2-A) forms a bridge between RAB27A on mature melanosomes and an actin-based motor myosin Va (MYO5A) and promotes subsequent actin-based melanosome transport [6, 7]. Mutations in the MYO5A (MIM*160777) encoding MYO5A and MLPH (MIM*606526) encoding MLPH/SLAC2-A cause other types of Griscelli syndrome GS-1 (MIM#214450) and GS-3 (MIM#609227), respectively [8, 9]. Unlike GS-2 patients, GS-1 patients reveal primary neurological problems, and GS-3 patients only exhibit pigmentary dilution
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