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Blood. 2016 Oct 27;128(17):2135-2143. Epub 2016 Aug 24.

Cytoskeletal abnormalities and neutrophil dysfunction in WDR1 deficiency.

Author information

1
Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD.
2
Laboratory of Host Defenses and.
3
Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD.
4
Werner H. Kirsten Student Internship Program, National Cancer Institute, NIH, Frederick, MD.
5
Hamad Medical Corporation, Doha, Qatar.
6
Baylor Institute for Immunology, Dallas, TX.
7
Cancer Research Technology Program, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD; and.
8
Center for Molecular Modeling, Center for Information Technology, NIH, Bethesda, MD.

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.

PMID:
27557945
PMCID:
PMC5084607
DOI:
10.1182/blood-2016-03-706028
[Indexed for MEDLINE]
Free PMC Article

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