Disruption of thrombocyte and T lymphocyte development by a mutation in ARPC1B

Raz Somech, Atar Lev, Yu Nee Lee, Amos J. Simon, Ortal Barel, Ginette Schiby, Camila Avivi, Iris Barshack, Michele Rhodes, Jiejing Yin, Minshi Wang, Yibin Yang, Jennifer Rhodes, Nufar Marcus, Ben Zion Garty, Jerry Stein, Ninette Amariglio, Gideon Rechavi, David L. Wiest*, Yong Zhang

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)4036-4045
Number of pages10
JournalJournal of Immunology
Issue number12
StatePublished - 15 Dec 2017


FundersFunder number
Commonwealth of PennsylvaniaCA100632
National Institutes of Health
National Cancer InstituteK22CA197014, P30CA006927, T32CA009035
National Institute of Allergy and Infectious DiseasesR21AI111208
Fox Chase Cancer CenterT32 CA009035


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