Cytoskeletal abnormalities and neutrophil dysfunction in WDR1 deficiency

Area of Science:

• Cellular biology
• Immunology
• Genetics

Background:

• Cellular cytoskeleton dynamics, including actin polymerization and depolymerization, are crucial for cell motility, division, and structural integrity.
• Actin polymerization and depolymerization are regulated by proteins like actin-interacting protein 1 (Aip1), which is essential for normal neutrophil function.

Observation:

• Four children from three families presented with recurrent infections, impaired wound healing, stomatitis, and distinctive neutrophil abnormalities, including nuclear lobe herniation and cytosol agranular regions.
• Patients exhibited impaired neutrophil chemotaxis and chemokinesis, but normal staphylococcal killing and enhanced oxidative burst.
• Neutrophil spreading and cell polarization were impaired, with a fourfold elevation in F-actin, suggesting dysregulation of actin.

Findings:

• Biallelic mutations in the WDR1 gene, encoding Aip1, were identified in all affected patients.
• These WDR1 mutations affected distinct antiparallel β-strands of Aip1, leading to abnormal protein function.
• The study confirmed an autosomal recessive inheritance pattern for WDR1 deficiency.

Implications:

• WDR1 mutations cause a novel primary immunodeficiency characterized by defective neutrophil morphology, motility, and function.
• Allogeneic stem cell transplantation successfully corrected the immunologic defect in one patient.
• Understanding WDR1's role in actin regulation provides insights into neutrophil function and primary immunodeficiencies.