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Published on: February 6, 2020
Cytoskeletal abnormalities and neutrophil dysfunction in WDR1 deficiency
Douglas B Kuhns1, Danielle L Fink1, Uimook Choi2
1Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD.
Insights
Genetic mutations in WDR1 cause a novel primary immunodeficiency by impairing neutrophil function. This actin-related protein 1 (Aip1) defect leads to recurrent infections and distinctive neutrophil abnormalities.
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.
Abstract:
Cell motility, division, and structural integrity depend on dynamic remodeling of the cellular cytoskeleton, which is regulated in part by actin polymerization and depolymerization. In 3 families, we identified 4 children with recurrent infections and varying clinical manifestations including mild neutropenia, impaired wound healing, severe stomatitis with oral stenosis, and death. All patients studied had similar distinctive neutrophil herniation of the nuclear lobes and agranular regions within the cytosol. Chemotaxis and chemokinesis were markedly impaired, but staphylococcal killing was normal, and neutrophil oxidative burst was increased both basally and on stimulation. Neutrophil spreading on glass and cell polarization were also impaired. Neutrophil F-actin was elevated fourfold, suggesting an abnormality in F-actin regulation. Two-dimensional differential in-gel electrophoresis identified abnormal actin-interacting protein 1 (Aip1), encoded by WDR1, in patient samples. Biallelic mutations in WDR1 affecting distinct antiparallel β-strands of Aip1 were identified in all patients. It has been previously reported that Aip1 regulates cofilin-mediated actin depolymerization, which is required for normal neutrophil function. Heterozygous mutations in clinically normal relatives confirmed that WDR1 deficiency is autosomal recessive. Allogeneic stem cell transplantation corrected the immunologic defect in 1 patient. Mutations in WDR1 affect neutrophil morphology, motility, and function, causing a novel primary immunodeficiency.
