title: Cytoskeletal abnormalities and neutrophil dysfunction in WDR1 deficiency.
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.
authors: Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD.
authors: Douglas B
authors: DB
authors: Kuhns
authors: Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD.
authors: Danielle L
authors: DL
authors: Fink
authors: Laboratory of Host Defenses and.
authors: Uimook
authors: U
authors: Choi
authors: Laboratory of Host Defenses and.
authors: Colin
authors: C
authors: Sweeney
authors: Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD.
authors: Karen
authors: K
authors: Lau
authors: Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD.
authors: Debra Long
authors: DL
authors: Priel
authors: Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD.
authors: Dara
authors: D
authors: Riva
authors: Neutrophil Monitoring Laboratory, Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD.
authors: Laura
authors: L
authors: Mendez
authors: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD.
authors: Gulbu
authors: G
authors: Uzel
authors: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD.
authors: Alexandra F
authors: AF
authors: Freeman
authors: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD.
authors: Kenneth N
authors: KN
authors: Olivier
authors: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD.
authors: Victoria L
authors: VL
authors: Anderson
authors: Werner H. Kirsten Student Internship Program, National Cancer Institute, NIH, Frederick, MD.
authors: Robin
authors: R
authors: Currens
authors: Werner H. Kirsten Student Internship Program, National Cancer Institute, NIH, Frederick, MD.
authors: Vanessa
authors: V
authors: Mackley
authors: Werner H. Kirsten Student Internship Program, National Cancer Institute, NIH, Frederick, MD.
authors: Allison
authors: A
authors: Kang
authors: Hamad Medical Corporation, Doha, Qatar.
authors: Mehdi
authors: M
authors: Al-Adeli
authors: Baylor Institute for Immunology, Dallas, TX.
authors: Emily
authors: E
authors: Mace
authors: Baylor Institute for Immunology, Dallas, TX.
authors: Jordan S
authors: JS
authors: Orange
authors: Laboratory of Host Defenses and.
authors: Elizabeth
authors: E
authors: Kang
authors: Cancer Research Technology Program, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD; and.
authors: Stephen J
authors: SJ
authors: Lockett
authors: Cancer Research Technology Program, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD; and.
authors: De
authors: Chen
authors: Center for Molecular Modeling, Center for Information Technology, NIH, Bethesda, MD.
authors: Peter J
authors: PJ
authors: Steinbach
authors: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD.
authors: Amy P
authors: AP
authors: Hsu
authors: Laboratory of Host Defenses and.
authors: Kol A
authors: KA
authors: Zarember
authors: Laboratory of Host Defenses and.
authors: Harry L
authors: HL
authors: Malech
authors: Laboratory of Host Defenses and.
authors: John I
authors: JI
authors: Gallin
authors: Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, MD.
authors: Steven M
authors: SM
authors: Holland
mesh_terms: D008841:Actin Cytoskeleton / Q000473:pathology*; D002648:Child; D015180:Electrophoresis, Gel, Two-Dimensional; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D015151:Immunoblotting; D007153:Immunologic Deficiency Syndromes / Q000276:immunology / Q000473:pathology*; D007960:Leukocyte Disorders / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008297:Male; D013058:Mass Spectrometry; D008840:Microfilament Proteins / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D018613:Microscopy, Confocal; D009154:Mutation; D009504:Neutrophils / Q000276:immunology / Q000473:pathology*; D010375:Pedigree
chemical_list: D008840:Microfilament Proteins; C118067:WDR1 protein, human