Systemic Inflammation and Normocytic Anemia in DOCK11 Deficiency

This original research identifies a previously unknown X-linked inborn error of immunity caused by rare germline loss-of-function mutations in DOCK11, which encodes a key actin cytoskeleton regulator. Studying four male patients from unrelated families, researchers observed severe immune dysregulation, recurrent infections, early-onset systemic inflammation, and normocytic anemia with abnormal erythrocyte morphology. Functional assays revealed impaired CDC42 activation, defective T-cell filopodia formation, abnormal migration, and proinflammatory cytokine overproduction linked to enhanced NFATc1 translocation. Erythroid defects were confirmed in DOCK11-deficient zebrafish and CD34+ human cells. Ectopic expression of active CDC42 rescued anemia phenotypes. The study concludes that DOCK11 mutations drive systemic inflammation and hematopoietic failure, expanding the spectrum of actin-related immunopathology.

This original research identifies a previously unknown X-linked inborn error of immunity caused by rare germline loss-of-function mutations in DOCK11, which encodes a key actin cytoskeleton regulator. Studying four male patients from unrelated families, researchers observed severe immune dysregulation, recurrent infections, early-onset systemic inflammation, and normocytic anemia with abnormal erythrocyte morphology. Functional assays revealed impaired CDC42 activation, defective T-cell filopodia formation, abnormal migration, and proinflammatory cytokine overproduction linked to enhanced NFATc1 translocation. Erythroid defects were confirmed in DOCK11-deficient zebrafish and CD34+ human cells. Ectopic expression of active CDC42 rescued anemia phenotypes. The study concludes that DOCK11 mutations drive systemic inflammation and hematopoietic failure, expanding the spectrum of actin-related immunopathology.