Molecular analysis and immunological characterization of a founder mutation causing ARPC1B deficiency

TL;DR

This study identifies a genetic mutation in ARPC1B that causes immune system deficiencies and explores its effects on immune cell populations.

Contribution

The study characterizes a founder mutation in ARPC1B and reveals its role in immune cell development and function.

Findings

The c.899_944del ARPC1B mutation leads to complete deficiency of the ARPC1B protein.

ARPC1B deficiency is associated with reduced frequencies of class-switched memory B cells and T cells.

The mutation impairs immune cell development and function, contributing to combined immunodeficiency.

Abstract

Actin-Related Protein Complex 1B (ARPC1B) is a subunit of the ARP2/3 complex that is predominately expressed in hematopoietic cells and is involved in the regulation of actin polymerization. ARPC1B deficiency leads to combined immunodeficiency (CID) with symptoms of eczema, allergies, inflammation, recurrent infection, and thrombocytopenia. We characterize the disease-causing variant c.899_944del (p.E300Gfs*7) on the ARPC1B gene that originated from a founder effect in an indigenous American population. We showed that this variant impairs protein expression leading to a complete deficiency of ARPC1B. Additionally, we used mass cytometry to thoroughly analyze the effects of this mutation on the frequencies of immune populations. Our findings suggest that ARPC1B is critical for class switching since our ARPC1B-deficient patient had reduced frequencies of class-switched memory B cells. Furthermore, the frequencies of total CD4+, CD8+, and γδ T cells were reduced, consistent with an essential function of ARPC1B in T cell development. Overall, this study advances the knowledge of the c.899_944del ARPC1B mutation and the understanding of the role of ARPC1B in the immune system.

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