Inherited ARPC5 mutations cause an actinopathy impairing cell motility and disrupting cytokine signaling

We describe the first cases of germline biallelic null mutations in ARPC5, part of the Arp2/3 actin nucleator complex, in two unrelated patients presenting with recurrent and severe infections, early-onset autoimmunity, inflammation, and dysmorphisms. This defect compromises multiple cell lineages and functions, and when protein expression is reestablished in-vitro, the Arp2/3 complex conformation and functions are rescued. As part of the pathophysiological evaluation, we also show that interleukin (IL)-6 signaling is distinctively impacted in this syndrome. Disruption of IL-6 classical but not trans-signaling highlights their differential roles in the disease and offers perspectives for therapeutic molecular targets. Mutations that impact the function of the Arp2/3 complex are known to cause inborn errors of immunity. Here the authors describe biallelic null mutations in the ARPC5 subunit of Arp2/3 that disrupt actin function and cytokine signaling, causing infections, autoimmunity, inflammation and dysmorphisms.

Automated summary

This study describes the first cases of germline biallelic null mutations in ARPC5, a subunit of the Arp2/3 actin nucleator complex. These mutations disrupt actin function and cytokine signaling, causing a range of symptoms including infections, autoimmunity, inflammation, and dysmorphisms. Additionally, the study demonstrates the distinctive impact of this syndrome on interleukin-6 (IL-6) signaling.