Inherited ARPC5 mutations cause an actinopathy impairing cell motility and disrupting cytokine signaling
Cristiane N. Santos, Hye Sun Kuehn, Brigette Boast, SuJin Hwang, Douglas B. Kuhns, Jennifer Stoddard, Julie E. Niemela, Danielle Fink, Stefania Pittaluga, Mones Abu‐Asab, John Davies, Valarie A. Barr, Tomoki Kawai, Ottavia M. Delmonte, Marita Bosticardo, Mary Garofalo, Magda Carneiro‐Sampaio, Raz Somech, Mohammad Gharagozlou, Nima Parvaneh, Lawrence E. Samelson, Thomas A. Fleisher, Anne Puel, Luigi D. Notarangelo, Bertrand Boisson, Jean‐Laurent Casanova, Beáta Dérfalvi, Sergio D. Rosenzweig
Abstract
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.