The Wiskott-Aldrich syndrome

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The Wiskott-Aldrich syndrome Hans D. Ochs, MD, Adrian J. Thrasher, MD, PhD Journal of Allergy and Clinical Immunology Volume 117, Issue 4, Pages 725-738 (April 2006) DOI: 10.1016/j.jaci.2006.02.005 Copyright © 2006 American Academy of Allergy, Asthma and Immunology Terms and Conditions

Fig 1 Schematic representation of the WASP gene, which encodes a protein with 12 exons and 5 major functional domains. The mutations identified in 270 unrelated WAS families are visualized according to their location in the exons and the exon-intron junctions. Each symbol represents a single family with WASP mutation. Missense mutations are located mostly in exons 1 through 4. Deletions, insertions, and nonsense mutations are distributed throughout the WASP gene. Splice-site mutations are found predominantly in introns 6, 8, 9, and 10. The symbols for specific WASP mutations shown in the box represent the 6 hot spots described in the text. EVH1, Ena/VASP homology 1 domain; BR, basic region; GBD, GTPase binding domain; PPPP, proline-rich region; VCA, verpolin cofilin homology domains/acidic region. Journal of Allergy and Clinical Immunology 2006 117, 725-738DOI: (10.1016/j.jaci.2006.02.005) Copyright © 2006 American Academy of Allergy, Asthma and Immunology Terms and Conditions

Fig 2 Model depicting mechanisms for activation of WASP. In the inactive state WASP adopts an autoinhibited configuration in which the C region of the verpoline cofilin homology domains/acidic region module interacts with the GTPase-binding domain and adjacent sequences. In this configuration either Arp2/3 complex cannot be bound or is inactive. Activation after cell stimulation is initiated by several factors, including GTP-bound CdC42, PIP2, and many SH3 domain–containing proteins that in some cases are responsible for phosphorylation of Y291. These individual factors might operate cooperatively but might also be redundant for activation, depending on the context. EVH1, Ena/VASP homology 1 domain; BR, basic region; GBD, GTPase-binding domain; VCA, verpoline cofilin homology domains/acidic region. Journal of Allergy and Clinical Immunology 2006 117, 725-738DOI: (10.1016/j.jaci.2006.02.005) Copyright © 2006 American Academy of Allergy, Asthma and Immunology Terms and Conditions

Fig 3 Flow cytometric analysis to assess WASP expression in peripheral blood lymphocytes. After permeabilization, as described by Yamada et al,38 lymphocytes are stained with polyclonal antibody 503 or an istotype control. Cells are then incubated with a second (anti-rabbit) antibody. Shown are a healthy control subject (top); a patient with a T deletion at position 1270, frame shift, and premature termination of transcription at codon 444 in the absence of WASP (center); and a patient with the missense mutation Arg86Cys, resulting in reduced WASP expression (bottom). Journal of Allergy and Clinical Immunology 2006 117, 725-738DOI: (10.1016/j.jaci.2006.02.005) Copyright © 2006 American Academy of Allergy, Asthma and Immunology Terms and Conditions