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Somech R , Lev A , Lee YN , Simon AJ , Barel O , Schiby G , Avivi C , Barshack I , Rhodes M , Yin J , Wang M , Yang Y , Rhodes J , Marcus N , Garty BZ , Stein J , Amariglio N , Rechavi G , Wiest DL , Zhang Y
Disruption of Thrombocyte and T Lymphocyte Development by a Mutation in ARPC1B
J Immunol. 2017 Nov 10;199(12) :4036-4045
PMID: 29127144    PMCID: PMC5726601    URL: https://www.ncbi.nlm.nih.gov/pubmed/29127144
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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.
Notes
1550-6606 Somech, Raz Lev, Atar Lee, Yu Nee ORCID: http://orcid.org/0000-0001-8648-5253 Simon, Amos J Barel, Ortal Schiby, Ginette Avivi, Camila Barshack, Iris Rhodes, Michele Yin, Jiejing Wang, Minshi ORCID: http://orcid.org/0000-0002-0225-0586 Yang, Yibin Rhodes, Jennifer ORCID: http://orcid.org/0000-0001-7298-1213 Marcus, Nufar Garty, Ben-Zion Stein, Jerry ORCID: http://orcid.org/0000-0001-6352-6956 Amariglio, Ninette Rechavi, Gideon Wiest, David L ORCID: http://orcid.org/0000-0002-0792-3188 Zhang, Yong Journal Article United States J Immunol. 2017 Nov 10. pii: jimmunol.1700460. doi: 10.4049/jimmunol.1700460.