ClinVar

In 3 unrelated patients with immunodeficiency-73B with defective neutrophil chemotaxis and lymphopenia (IMD73B; 618986), Hsu et al. (2019) identified a de novo heterozygous c.184G-A transition in exon 3 of the RAC2 gene, resulting in a glu62-to-lys (E62K) substitution in the highly conserved Switch II domain. The mutation, which was found by exome sequencing or targeted sequencing of a gene panel, was confirmed by Sanger sequencing in all cases. Patient neutrophils and cells transfected with the mutation had increased production of reactive oxygen species (ROS), both at a basal rate and in response to fMLF. Additional abnormalities included impaired fMLF-induced chemotaxis, increased ruffling, abnormal actin cycling, and large vesicle formation in neutrophils. Further studies suggested that E62K favors the active GTP-bound state and causes impaired GTP hydrolysis compared to wildtype, resulting in prolonged activation of downstream effectors. The mutation resulted in a dominant gain-of-function effect.

In 3 members of a 3-generation family with IMD73B, Smits et al. (2020) identified a heterozygous E62K mutation in the RAC2 gene. In vitro studies of patient neutrophils showed defective migration and reduced bacterial killing. However, there was an increase of GTP-bound RAC2 after fMLF stimulation compared to controls, consistent with a gain-of-function activating effect. T-cell subsets showed increased effector T cells and decreased recent thymic emigrant cells, suggesting disturbances in RAC2 signal-mediated chemotactic function of T cells. The authors suggested that increased GTP-bound RAC2 may impede physiologic actin polymerization.