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

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 multi-subunit 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 (WES) revealed a homozygous 2 bp deletion, n.c.G623DEL-TC (p.V208fs), 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.V208fs variant identified in the patient. 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, while mutations in other, more widely expressed, components of the Arp2/3 complex have not been observed.

Targeted NGS Platforms for Genetic Screening and Gene Discovery in Primary Immunodeficiencies

“…The first 6 diagnoses were obtained in a cohort of 32 patients. Three SCID/CID patients with mutations in RAG1, IL7R and ARPC1B genes [ (40,(45)(46)(47) and Volpi et al, under revision] were diagnosed in 8 T cell defects (37,5%). Moreover, JAGN1 (48), CECR1 (43) and NRAS genes, associated to complex phenotypes, were identified in 12 of the Other PIDs group (25%) (Figure 3C).…”

Primary immunodeficiencies caused by mutations in actin regulatory proteins

“…There are two isoforms of the ARPC1 protein encoded by the two tandem ARPC1A and ARPC1B genes. ARPC1B is strongly expressed in human bone marrow . Branched actin filaments associated with ARP2/3 complexes containing ARPC1B have increased Cortactin binding and stability .…”

“…Mice deficient in ARPC1B have normal development of T cells and platelets but develop hyper‐IgE and vasculitis. In zebra fish, Arpc1b has been shown to be important for both T cell and platelet development …”

“…Three reports have described patients with mutations in the ARPC1B genes . While the immune phenotype was variable, all patients had thrombocytopenia.…”

“…ARPC1B is strongly expressed in human bone marrow. 120 Branched actin filaments associated with ARP2/3 complexes containing ARPC1B have increased…”