RRC ID 63350
Author Ohishi Y, Ammann S, Ziaee V, Strege K, Groß M, Amos CV, Shahrooei M, Ashournia P, Razaghian A, Griffiths GM, Ehl S, Fukuda M, Parvaneh N.
Title Griscelli Syndrome Type 2 Sine Albinism: Unraveling Differential RAB27A Effector Engagement.
Journal Front Immunol
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.
Volume 11
Pages 612977
Published 2020-1-1
DOI 10.3389/fimmu.2020.612977
PMID 33362801
PMC PMC7758216
MeSH Adaptor Proteins, Signal Transducing / genetics Adolescent Albinism / genetics* Animals Binding Sites / genetics COS Cells Cell Line Child Child, Preschool Chlorocebus aethiops Female Humans Infant Infant, Newborn Leukocytes, Mononuclear / metabolism Lymphohistiocytosis, Hemophagocytic / genetics* Male Membrane Proteins / genetics Mutation, Missense / genetics Piebaldism / genetics* Primary Immunodeficiency Diseases / genetics* rab GTP-Binding Proteins / genetics rab27 GTP-Binding Proteins / genetics*
IF 5.085
DNA material pMRX-bsr-EGFP-hRab27A (RDB18647) pMRX-bsr-EGFP-hRab27A-V143A (RDB18648)