Laboratory of Membrane Trafficking Mechanisms, Department of Integrative Life Sciences, Graduate School of Life Sciences, Tohoku University, Sendai, Japan.
Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Faculty of Medicine, Medical Center-University of Freiburg, University of Freiburg, Freiburg, Germany.
Front Immunol. 2020 Dec 10;11:612977. doi: 10.3389/fimmu.2020.612977. eCollection 2020.
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 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 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.
Griscelli 综合征 2 型（GS-2）是一种免疫遗传性疾病，其特征为部分白化病和噬血细胞性淋巴组织细胞增生症（HLH）发作。它是由编码 Rab GTPase 家族成员 RAB27A 的 突变引起的。RAB27A 在许多组织中表达，调节囊泡运输和细胞器动力学。偶尔，携带 RAB27A 突变的 GS-2 患者显示正常的色素沉着。对这些变体的研究为 RAB27A 上组织特异性效应器的不同结合位点提供了机会。在这里，我们提出了一个新的无白化病 GS-2 病例（GS-2 sine albinism），该病例由 RAB27A 中的新错义突变（Val143Ala）引起，并对其功能细胞后果进行了表征。使用相关的动物细胞系，Val143Ala 突变既损害了 RAB27A-SLP2-A 相互作用，也损害了 RAB27A-MUNC13-4 相互作用，但不影响对皮肤和头发色素沉着至关重要的 RAB27A-黑素磷蛋白（MLPH）/SLAC2-A 相互作用。我们得出结论，破坏细胞毒性淋巴细胞中的 RAB27A-MUNC13-4 相互作用导致携带 Val143Ala 突变的 GS-2 患者易患 HLH。最后，我们对文献中报道的 GS-2 sine albinism 病例进行了综述，总结了它们的遗传和临床特征。
