title: Macrophages of patients with X-linked thrombocytopenia display an attenuated Wiskott-Aldrich syndrome phenotype.
abstract: The immunodeficiency disorder Wiskott-Aldrich syndrome and its milder form X-linked thrombo-cytopenia are caused by mutations in the WASp gene. Wiskott-Aldrich syndrome is characterized by a plethora of clinical symptoms which are due to functional defects of haematopoietic cells, including the inability of macrophages to form actin-rich adhesion structures called podosomes. In contrast, X-linked thrombocytopenia patients show reduced platelet size and counts but no cytoskeletal white blood cell defects have been detected so far. Here we use immunofluorescence technique to evaluate podosome formation in macrophages from X-linked thrombocyto-penia and Wiskott-Aldrich syndrome patients and from healthy donors. We find that X-linked thrombocytopenia macrophages, cells previously thought to be unaffected in this disorder, are compromised in the formation of podosomes. Western blot analysis shows that this phenotype is not due to lower levels of WASp expression. Interestingly, the bacterial chemoattractant formyl-methionyl-leucyl-phenylalanine can rescue podosome formation in X-linked thrombocytopenia cells. Our findings indicate that: 1. The spectrum of WASp-dependent disorders contains defects more subtle than originally recognized and 2. in X-linked thrombocytopenia, some of these defects may not be evident under conditions of bacterial stimulation. Further evaluation of this and other, as yet unrecognized, cellular defects may provide a more complete picture of the continuum of Wiskott-Aldrich syndrome and X-linked thrombocytopenia defects.
authors.affiliation: Institut für Prophylaxe und Epidemiologie der Kreislaufkrankheiten, Ludwig-Maximilians-Universität, Dr von Haunersches Kinderspital, Klinikum Innenstadt, Lindwurmstr, München, Germany. stefan.linder@klp.med.uni-muechen.de
authors.forename: Stefan
authors.initials: S
authors.lastname: Linder
authors.forename: Uwe
authors.initials: U
authors.lastname: Wintergerst
authors.forename: Christine
authors.initials: C
authors.lastname: Bender-Götze
authors.forename: Klaus
authors.initials: K
authors.lastname: Schwarz
authors.forename: Ulrich
authors.initials: U
authors.lastname: Pannicke
authors.forename: Martin
authors.initials: M
authors.lastname: Aepfelbacher
mesh_terms: D016022:Case-Control Studies; D048429:Cell Size; D002648:Child; D003599:Cytoskeleton / Q000473:pathology; D040181:Genetic Diseases, X-Linked / Q000473:pathology; D006801:Humans; D007223:Infant; D008264:Macrophages / Q000473:pathology*; D008297:Male; D008856:Microscopy, Fluorescence; D009240:N-Formylmethionine Leucyl-Phenylalanine / Q000494:pharmacology; D010641:Phenotype; D011506:Proteins / Q000032:analysis; D013921:Thrombocytopenia / Q000235:genetics / Q000473:pathology*; D014923:Wiskott-Aldrich Syndrome / Q000473:pathology*; D051316:Wiskott-Aldrich Syndrome Protein
chemical_list: D011506:Proteins; C495767:WAS protein, human; D051316:Wiskott-Aldrich Syndrome Protein; D009240:N-Formylmethionine Leucyl-Phenylalanine