Cytoskeletal abnormalities and neutrophil dysfunction in WDR1 deficiency.
2016
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
neutrophilherniation of the nuclear lobes and agranular regions within the cytosol. Chemotaxis and
chemokinesiswere markedly impaired, but staphylococcal killing was normal, and
neutrophiloxidative burst was increased both basally and on stimulation.
Neutrophilspreading on glass and
cell polarizationwere also impaired.
NeutrophilF-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
neutrophilfunction. 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
neutrophilmorphology, motility, and function, causing a novel
primary immunodeficiency.
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