ARPC5 deficiency leads to severe early-onset systemic inflammation and mortality

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Elena Sindram Andrés Caballero-Oteyza Naoko Kogata Shaina Huang Zahra Alizadeh Laura Gámez-Díaz Mohammad Reza Fazlollhi Xiao Peng Bodo Grimbacher Michael Way Michele Proietti
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Abstract

The Arp2/3 complex drives the formation of branched actin networks that are essential for many cellular processes. In humans, the ARPC5 subunit of the Arp2/3 complex is encoded by two paralogous genes (ARPC5 and ARPC5L) with 67% identity. Through whole-exome sequencing, we identified a biallelic ARPC5 frameshift variant in a female child who presented with recurrent infections, multiple congenital anomalies, diarrhea, and thrombocytopenia, and suffered early demise from sepsis. Her consanguineous parents also had a previous child who died with similar clinical features. Using CRISPR/Cas9-mediated approaches, we demonstrate that loss of ARPC5 affects actin cytoskeleton organization and function in vitro. Homozygous Arpc5-/- mice do not survive past embryonic day 9 due to developmental defects, including loss of the second pharyngeal arch which contributes to craniofacial and heart development. Our results indicate that ARPC5 is important for both prenatal development and postnatal immune signaling, in a non-redundant manner with ARPC5L. Moreover, our observations add ARPC5 to the list of genes that should be considered when patients present with syndromic early-onset immunodeficiency, particularly if recessive inheritance is suspected.

Journal details

Journal Disease Models and Mechanisms
Volume 16
Issue number 7
Pages dmm050145
Available online
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Publisher website (DOI) 10.1242/dmm.050145
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Europe PubMed Central 37382373
Pubmed 37382373

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The publication was previously a preprint. View preprint