HEM1 Actin Immunodysregulatory Disorder: Genotypes, Phenotypes, and Future Directions

Abstract

AbstractCells of the innate and adaptive immune systems depend on proper actin dynamics to control cell behavior for effective immune responses. Dysregulated actin networks are known to play a pathogenic role in an increasing number of inborn errors of immunity. The WAVE regulatory complex (WRC) mediates branched actin polymerization, a process required for key cellular functions including migration, phagocytosis, vesicular transport, and immune synapse formation. Recent reports of pathogenic variants in NCKAP1L, a hematopoietically restricted gene encoding the HEM1 protein component of the WRC, defined a novel disease involving recurrent bacterial and viral infections, autoimmunity, and excessive inflammation (OMIM 141180). This review summarizes the diverse clinical presentations and immunological phenotypes observed in HEM1-deficient patients. In addition, we integrate the pathophysiological mechanisms described in current literature and highlight the outstanding questions for diagnosis and management of the HEM1 actin immunodysregulatory disorder.