Genetic characteristics of eighty-seven patients with the Wiskott–Aldrich syndrome

Disruption of hSWI/SNF complexes in T cells by WAS mutations distinguishes X-linked thrombocytopenia from Wiskott-Aldrich syndrome

“…3 In Xenopus oocytes, the gene activation function of Wave1, a WASp-family protein, is also independent of its VCA-like (verprolin-homology) domain. 12 Although these findings align well with the observation that VCA-domain missense mutations generally do not result in XLT-to-WAS progression in humans, [6][7][8][9] the question remains: why are some WAS mutations more pathogenic to the immune system whereas others spare it completely? Answering this will require clarifying the mechanism(s) by which WASp functions in the nucleus of human T H cells and other immune cells, and how individual WAS mutations differ in their proclivity to perturb this process.…”

“…Mutations in PH-domain (S24F), WH1-domain (T45M, R86C), basic-domain (A236G, D224G), and VCA-domain (K476E, R477K) all reported to result in at least XLT were selected ( Figure 2A and supplemental Figure 3A). [6][7][8][9] Similar to FL-WASp, all mutants translocate to the nucleus in T H 1-and TCR-activation-dependent manner (reported by pTyr319 ZAP70) because their association with importin-b1 remains intact (supplemental Figure 3D-E).…”

“…Notably, WAS genotypephenotype correlations show a predilection for missense mutations occurring in WASp-homology1(WH1)-domain but not VCA-domain to manifest XLT-to-WAS disease progression. [6][7][8][9] Such observations suggest novel, VCA:ARP2/3-independent function(s) of WASp in immunobiology, whose impairment we postulate contributes to the development of XLT-to-WAS cross-phenotype (CP) progression. 5 Elucidating the underlying mechanism for the CP effect in WAS is a major challenge in the field.…”

“…5 Loss-of-function mutations associate with X-linked thrombocytopenia (XLT), a platelet defect presenting with bleeding symptoms, or WAS, where, in addition to thrombocytopenia, immunodeficiency, autoimmunity, and cancer predominate. [6][7][8][9] In WAS, multiple cell-lineages of the immune system are affected. 10 Gain-offunction mutations associate with X-linked neutropenia (XLN), a white-cell defect presenting with infections.…”

Wiskott-Aldrich syndrome mutation in two Turkish siblings with X-linked thrombocytopenia

“…The WASP gene encodes WASP, a 502 amino acid protein that plays a critical role actin cytoskeleton organization, signaling, and immune cell function [5]. This protein has multiple functional domains used in actin polymerization, cellular motility, intracellular signaling, and apoptosis [6].…”