TY - JOUR
T1 - Griscelli Syndrome Type 2 Sine Albinism
T2 - Unraveling Differential RAB27A Effector Engagement
AU - Ohishi, Yuta
AU - Ammann, Sandra
AU - Ziaee, Vahid
AU - Strege, Katharina
AU - Groß, Miriam
AU - Amos, Carla Vazquez
AU - Shahrooei, Mohammad
AU - Ashournia, Parisa
AU - Razaghian, Anahita
AU - Griffiths, Gillian M.
AU - Ehl, Stephan
AU - Fukuda, Mitsunori
AU - Parvaneh, Nima
N1 - Funding Information:
We thank Jonathan Kaufman for helping to configure the RAB27A 3D structure, Nasrin Alipour for bioinformatics assistance, and Herman Waldmann and Toshio Kitamura for kindly donating materials.
Funding Information:
This work was supported in part by Grant-in-Aid for Scientific Research (B) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan (grant number 19H03220 to MF), and by Japan Science and Technology Agency (JST) CREST (grant number JPMJCR17H4 to MF).
Publisher Copyright:
© Copyright © 2020 Ohishi, Ammann, Ziaee, Strege, Groß, Amos, Shahrooei, Ashournia, Razaghian, Griffiths, Ehl, Fukuda and Parvaneh.
PY - 2020/12/10
Y1 - 2020/12/10
N2 - 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.
AB - 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.
KW - Griscelli syndrome type 2 sine albinism
KW - MLPH/SLAC2-A
KW - MUNC13-4
KW - RAB27A
KW - hemophagocytic lymphohistiocytosis
KW - inborn error of immunity
KW - whole-exome sequencing
UR - http://www.scopus.com/inward/record.url?scp=85098175402&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85098175402&partnerID=8YFLogxK
U2 - 10.3389/fimmu.2020.612977
DO - 10.3389/fimmu.2020.612977
M3 - Article
C2 - 33362801
AN - SCOPUS:85098175402
SN - 1664-3224
VL - 11
JO - Frontiers in Immunology
JF - Frontiers in Immunology
M1 - 612977
ER -