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J Immunol. 2017 Dec 15;199(12):4036-4045. doi: 10.4049/jimmunol.1700460. Epub 2017 Nov 10.

Disruption of Thrombocyte and T Lymphocyte Development by a Mutation in ARPC1B.

Author information

1
Pediatric Department A and Immunology Service, Jeffrey Modell Foundation Center, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 52621, Israel.
2
The Wohl Institute for Translational Medicine, Sheba Medical Center, Tel Hashomer, Tel Aviv 52621, Israel.
3
Hematology Laboratory, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 52621, Israel.
4
Sheba Cancer Research Center, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 52621, Israel.
5
Department of Pathology, Sheba Medical Center, Tel Hashomer, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 52621, Israel.
6
Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA 19111.
7
Allergy and Immunology Unit, Schneider Children's Medical Center of Israel, Felsenstein Medical Research Center, Kipper Institute of Immunology, Petach Tikva, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 4920235, Israel.
8
Bone Marrow Transplantation Unit, Schneider Children's Medical Center of Israel, Petach Tikva, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 4920235, Israel; and.
9
The Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan 52900, Israel.
10
Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA 19111; yong.zhang@fccc.edu david.wiest@fccc.edu.

Abstract

Regulation of the actin cytoskeleton is crucial for normal development and function of the immune system, as evidenced by the severe immune abnormalities exhibited by patients bearing inactivating mutations in the Wiskott-Aldrich syndrome protein (WASP), a key regulator of actin dynamics. WASP exerts its effects on actin dynamics through a multisubunit complex termed Arp2/3. Despite the critical role played by Arp2/3 as an effector of WASP-mediated control over actin polymerization, mutations in protein components of the Arp2/3 complex had not previously been identified as a cause of immunodeficiency. Here, we describe two brothers with hematopoietic and immunologic symptoms reminiscent of Wiskott-Aldrich syndrome (WAS). However, these patients lacked mutations in any of the genes previously associated with WAS. Whole-exome sequencing revealed a homozygous 2 bp deletion, n.c.G623DEL-TC (p.V208VfsX20), in Arp2/3 complex component ARPC1B that causes a frame shift resulting in premature termination. Modeling of the disease in zebrafish revealed that ARPC1B plays a critical role in supporting T cell and thrombocyte development. Moreover, the defects in development caused by ARPC1B loss could be rescued by the intact human ARPC1B ortholog, but not by the p.V208VfsX20 variant identified in the patients. Moreover, we found that the expression of ARPC1B is restricted to hematopoietic cells, potentially explaining why a mutation in ARPC1B has now been observed as a cause of WAS, whereas mutations in other, more widely expressed, components of the Arp2/3 complex have not been observed.

PMID:
29127144
PMCID:
PMC5726601
[Available on 2018-12-15]
DOI:
10.4049/jimmunol.1700460
[Indexed for MEDLINE]

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