Understanding immunoactinopathies: A decade of research on WAS gene defects

Abstract

AbstractImmunoactinopathies caused by mutations in actin‐related proteins are a growing group of inborn errors of immunity (IEI). Immunoactinopathies are caused by a dysregulated actin cytoskeleton and affect hematopoietic cells especially because of their unique capacity to survey the body for invading pathogens and altered self, such as cancer cells. These cell motility and cell‐to‐cell interaction properties depend on the dynamic nature of the actin cytoskeleton. Wiskott‐Aldrich syndrome (WAS) is the archetypical immunoactinopathy and the first described. WAS is caused by loss‐of‐function and gain‐of‐function mutations in the actin regulator WASp, uniquely expressed in hematopoietic cells. Mutations in WAS cause a profound disturbance of actin cytoskeleton regulation of hematopoietic cells. Studies during the last 10 years have shed light on the specific effects on different hematopoietic cells, revealing that they are not affected equally by mutations in the WAS gene. Moreover, the mechanistic understanding of how WASp controls nuclear and cytoplasmatic activities may help to find therapeutic alternatives according to the site of the mutation and clinical phenotypes. In this review, we summarize recent findings that have added to the complexity and increased our understanding of WAS‐related diseases and immunoactinopathies.