Database for Annotation, Visualization and Integrated Discovery 2.1
National Institute of Allergy and Infectious Disease
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Wiskott-Aldrich syndrome(WAS) Wiskott-Aldrich syndrome(WAS) Related Genes Homo sapiens
CYTOBAND Xp11.4-p11.21,
GENERIF_SUMMARY WASp mediates actin polymerization and leads to ultimately to occupancy-induced TCR endocytosis, mutational analysis in patients with Wiskott-Aldrich syndrome in Argentina, Missense mutations of the WASP gene cause intermittent X-linked thrombocytopenia, Normal chemotactic responses were restored in WASp macrophages transfected with a full-length human WAS construct. Expression of exogenous WAS protein (WASp) in these cells also restored normal polarised cell morphology and the ability to form podosomes., An Alu-mediated deletion at Xp11.23 leading to Wiskott-Aldrich syndrome., Five novel WASP mutations have been identified that are all predicted to lead to premature translational termination of the WAS protein., Activation of Wiskott-Aldrich syndrome protein and its association with other proteins by stromal cell-derived factor-1alpha is associated with cell migration in Jurkat cells, a T-lymphocyte line., Required for NK cell cytotoxicity and colocalizes with actin to NK cell-activating immunologic synapses, Wiskott-Aldrich Syndrome protein regulates lipid raft dynamics during immunological synapse formation, Platelets activate Arp2/3 complex, assemble actin, and change shape in the absence of WASp, indicating a more specialized role for WASp in these cells., Data show that the Src family kinase Hck induces phosphorylation of Wiskott Aldrich syndrome protein (WASp)-Tyr(291) independently of Cdc42 and that this causes a shift in the mobility of WASp upon SDS-PAGE., mutated in Wiskott Aldrich syndrome, Results suggest that recruitment of factors by Wiskott-Aldrich Syndrome protein (WASP) and Scar1 stimulates cellular actin-based motility and actin nucleation with the Arp2/3 complex., results suggest that the ZAP-70-CrkL-WIP pathway and PKCtheta link TCR to WASP activation, PSTPIP1 acts downstream of CD2/CD2AP to link CD2 engagement to the WASp-evoked actin polymerization required for synapse formation and T cell activation., X-linked thrombocytopenia caused by a mutation in the WAS gene that disrupts interaction with the (WASP)-interacting protein (WIP)., Results describe somatic mosaicism in two brothers affected with Wiskott-Aldrich syndrome (WAS) due to a second-site mutation in the WAS protein (WASP) gene., Phosphorylation plays a critical role in WASP function as a regulator of arp-2- and arp-3-mediated actin polymerization., WAS protein expression is a useful tool for predicting long-term prognosis for patients with Wiskott-Aldrich syndrome., Differentiation and survival of B lymphocytes is minimally dependent on WAS protein., the interaction of the betaPIX.WASP.SPIN90 complex with Nck is crucial for stable cell adhesion and can be dynamically modulated by SPIN90 phosphorylation that is dependent on cell adhesion and ERK activation, WASp undergoes tyrosine phosphorylation upon CD16 or beta2-integrin engagement on NK cells., WASp is either not involved in or is redundant in the rapid dynamics of lymphocyte microvilli., interactions of WASP and WIP are affected by two novel mutations that change the conformation of WASP and disrupt hydrogen bonding, Mutations identified included p.R13X, p.R41X, p.S82P, IVS1-1 G --> C, p.L342TFsX493, and a large deletion., The Wiskott-Aldrich WASP protein is an important component for integration of signals leading to nuclear translocation of transcription factors NFAT2 and NF-kappa B RelA during cell-cell contact and natural cytotoxicity receptor NKp46-dependent signaling., Results describe a quantitative model of allosteric regulation of the Wiskott-Aldrich syndrome protein (WASP) by the Rho GTPase Cdc42., The selective advantage of WASP+ natural killer cells was also demonstrated for carrier females, Knowledge of the molecular effect of WAS protein mutations provides a logical basis for correlating genotype and clinical phenotype of Wiskott-Aldrich syndrome, The process is a prerequisite for WASp activation and a critical step in temporal regulation and integration of WASp-mediated cellular responses., TRAP and WASp, but not other unrelated aldolase binders, compete for the binding to the enzyme in vitro., NMR investigation and cross-linking studies of the interaction of the Arp2/3 complex with VCA peptides of Wiskott-Aldrich syndrome protein, WASP and N-WASP are activated and phosphorylated by protein-tyrosine kinase and GTPase signals, A partial down-regulation of WASP is sufficient to inhibit podosome formation in dendritic cells., A novel Wiskott-Aldrich syndrome protein (WASP) complex mutation identified in a WAS patient results in an aberrant product at the C-terminus from two transcripts with unusual polyA signals., Human WASP suppresses the growth defect of Saccharomyces cerevisiae las17Delta strain, only in the presence of WASP-interacting protein (WIP)., The results strongly suggest that the smaller WASP is translated from the second ATG downstream of the original mutation, and not only T cells but also NK cells carrying the second mutation acquired a growth advantage over WASP negative counterparts., WASP binds to the calcium- and integrin-binding protein (CIB) in platelets., In addition to chemotaxis, the WASP-verprolin complex is involved in both podosome formation and phagocytosis., activating mutations in the Wiskott-Aldrich syndrome protein result in congenital neutropenia, impaired beta2 integrin function in WASp-deficient neutrophil may contribute substantially to the clinical immunodeficiency suffered by WAS patients, investigated family members of the patients originally described by Wiskott in 1937 and identified a new frame shift mutation in exon 1 of WAS, the WASp/SNX9/p85/CD28 complex enables a unique interface of endocytic, actin polymerizing, and signal transduction pathways required for CD28-mediated T cell costimulation, Thus, WASP appears to play an important role in the activation and suppressor function of nTreg cells, and a dysfunction or incorrect localization of nTreg cells may contribute to the development of autoimmunity in WAS patients., Two novel mutations of the WASP gene in two Spanish families with patients clinically diagnosed as havingX-linked thrombocytopenia and Wiskott-Aldrich syndrome, were identified., study found 28 novel WAS mutations in Wiskott-Aldrich syndrome and X-linked thrombocytopenia (7 missense, 1 nonsense, 1 nonstop change, 5 splice site mutations and 14 deletions or insertions), Chinese Wiskott-Aldrich Syndrome (WAS) patients had mutations involving exon 1 of the Wiskott-Aldrich syndrome protein (WASP) gene and none had the X-linked thrombocytopenia phenotype., the WIP-WASP complex plays an important role in WASP stabilization and NFAT activation, Study provides a strategy that allows a strong suppression of WASp in CD34(+) cells and will facilitate future studies on the role of WASp in human cells., These findings reveal a novel mechanism for inhibition of myelopoiesis through defective mitosis and cytokinesis due to hyperactivation and mislocalization of actin polymerization., that WASP and WASP-interacting protein (WIP) form a complex at the phagocytic cup and that the WASP.WIP complex plays a critical role in the phagocytic cup formation., The discovery of unique functional domains of Wiskott-Aldrich syndrome protein has been instrumental in defining mechanisms that control activation of Wiskott-Aldrich syndrome protein. Review., Genotypic analysis of allospecific T-cell clones revealed a remarkable diversity of deletions and base substitutions resulting in at least 34 different revertant genotypes that restored expression of WASp, One gene with unknown function to be differentially expressed in UC but not Crohn's disease by RT-PCR. Due to its predicted protein architecture, we call this gene Wiskott-Aldrich syndrome protein., the presence of truncated WASP confers an extreme disadvantage in early developing thymocytes, beyond that of absence of full-length WASP, and the disadvantage likely occurs through dominant negative competition of WASP Delta VCA with N-WASP, Robo4 binding to a Wiskott-Aldrich syndrome protein (WASP), Dimerization act in hierarchical fashion, enabling WASP/WAVE proteins to integrate different classes of inputs to produce a wide range of cellular actin responses in Wiskoo Aldrich syndrome., data from this large pedigree with the WAS I294T mutation provide new independent genetic evidence that mutations disrupting the auto-inhibitory GTP-ase binding domain of WASP are the cause of X-linked neutropenia, formin-binding protein 17 (FBP17) recruits WASP, WASP-interacting protein (WIP), and dynamin-2 to the plasma membrane and that this recruitment is necessary for the formation of podosomes and phagocytic cups., SNX33 plays a role in maintaining cell shape and cell cycle progression through its interaction with WASp, CSF-1-induced WASP activation was fully Cdc42-dependent., Was cDNA sequences increased the hematopoietic specificity of Was promoter-driven lentiviral vector., Cdc42 binding and activation of WASp are required for podosome formation and chemotaxis., The results suggest that some of the mutations in the WH1 domain cause the Wiskott-Aldrich syndrome syndrome in humans by perturbing the WASP-WIP complex formation., a clustering pattern on exon 1 and five unique mutations explain the genetic variations in different ethnic groups, Lymphocytes isolated from a patient with WASP(I294T), and in a cellular model of WASP(I294T), displayed abnormal microvillar architecture, associated with an increase in total cellular F-actin., A nuclear role for WASp in the transcriptional regulation of the TH1 regulator gene TBX21 at the chromatin level, was discovered., WASP is key in transducing signals from the cell surface to the actin cytoskeleton, and a lack of WASp results in cytoskeletal defects that compromise multiple aspects of normal cellular activity. Review., mutations were scattered throughout the WASP gene and included single base pair changes (17 missense and 11 nonsense mutations), 7 small insertions, 18 deletions, and 9 splice site defects, WAVE2 and WASp define parallel pathways to F-actin reorganization and function in NK cells; although WAVE2 was not required for NK cell innate function, it was accessible through adaptive immunity via IL-2., activation of the Arp2/3 complex by the conserved VCA domain of WASP most likely involves engagement of two distinct sites on Arp2/3 complex by two VCA molecules, each delivering an actin monomer. One site is on Arp3 and the second is on ARPC1 and Arp2, WASp-deficiency compromised the ability of Wiskott-Aldrich DCs to prime T cells to react appropriately, Genetic complementation with transduced human WASp restored functionality., the c.273+11dup change within the WAS gene was observed in patients showing symptoms consistent with the Wiskott-Aldrich syndrome; concluded that the presence of the additional C in the WAS gene is a functionally neutral polymorphism, Mutation in WASP gene is associated with Wiskott-Aldrich syndrome and X-linked thrombocytopenia., The wild-type WASp, but not the mutant restored adhesion capacity, spreading morphology, and cytoskeletal reorganization., study describes that both N-WASp and WASp participate in the inhibition of NK-cell chemotaxis in response to NKG2D WASp engagement, and that this effect is not dependent on the regulation of F-actin dynamics, data suggest that regulated degradation of activated WASp might be an efficient strategy by which the duration and localization of actin rearrangement and the intensity of T-cell activation are controlled., WASP-deficient T cells migrated in a normal proportion towards CXCL12, CCL19 and CCL21, but displayed an increased adhesion and elongation on ICAM-1, Data indicate that slit2N alters the localization and binding of Robo1 to WASp and LSP1 in HIV-1-gp120-treated immature dendritic cells (iDCs)., Despite mediating enhanced actin polymerization, EVH1 missense-mutated human proteins did not function fully in mouse cells, even when overexpressed. Mutant protein retention in podosomes was impaired & associated with low WASp Tyr phosphorylation., this is the first report describing TTP in WAS patients with novel mutation in the WASP gene., Report five previously reported mutations and six novel mutations in WASP gene in Iranian Wiskott-Aldrich patients., We present two cases of WAS in neonates with WAS gene mutations, Dedicator of cytokinesis 8 interacts with talin and Wiskott-Aldrich syndrome protein to regulate NK cell cytotoxicity., Missense mutation in the WAS gene is associated with intermittent X-linked thrombocytopenia., We conclude that WASp function restricts TGF-b1 secretion in a Cdc42- and Src family kinase-dependent manner and independently of actin assembly, WASP deficiency perturbs the homeostasis of B-cell compartment in humans., Pro373Ser mutation reduces Tyr291 phosphorylation and prevents conformational changes required for WASP activity in chemotaxis and T-cell activation., study unveils an ARP2/3, These findings support a contributory role for defective Breg cells in the development of WAS-related autoimmunity, Data indicate the WASp-interacting protein (WIP)-Wiskott-Aldrich syndrome protein (WASp) interaction in the regulation of actin-dependent processes., N-WASP is downregulated in clear cell renal cell carcinoma, WAS gene mutation is associated with X-linked thrombocytopenia in three males with normal sized platelets., Data indicate that mycolactone analogues bind Wiskott-Aldrich syndrome proteins (WASP} with IC50 in the 50-10 muM range., data suggest that missense mutations WASPRL46P or WASPRA47D affect the activity of WASP in T cell chemotaxis probably by affecting the turnover of the protein., An indispensable relationship between nuclear-WASp- and hSWI/SNF-complexes in gene activation and molecular distinctions in TH cells that might contribute to disease severity in the X-linked thrombocytopenia/Wiskott-Aldrich syndrome clinical spectrum., studies discovered that HMGB1 suppressed phosphorylation, nuclear translocation, and activation of CREB, by inhibiting nuclear translocation of PKA catalytic subunit, WASp and WAVE2 differ in their dynamics and their associated proteins, conclude that tyrosine phosphorylation of WIP is a crucial regulator of WASP stability and function as an actin-nucleation-promoting factor, A total of 60 unique WAS mutations were identified in Chinese patients, including 20 novel mutations and 8 hotspots, from 75 unrelated families with a total of 81 affected members., Platelet actin nodule formation is dependent on WASp and the ARP2/3 complex., Studies indicate that mutations in the Wiskott-Aldrich syndrome protein (WASp) gene cause a continuum of clinical symptoms ranging from intermittent X-linked thrombocytopenia to full classical Wiskott-Aldrich syndrome (WAS)., WASP, RUNX1, and ANKRD26 genes are important for normal TPO signaling and the network underlying thrombopoiesis., we identify small ubiquitin-related modifier (SUMO)ylation as a novel posttranslational modification of WASp, We describe two Malay patients with classical Wiskott-Aldrich Syndrome with two different mutations in the WASP gene, The introduction of functional WASp by GT corrected the alterations of both central and peripheral B cell tolerance checkpoints. WASp plays an important role in the establishment and maintenance of B cell tolerance in humans., This suggests that N-WASP's failure to compensate for WASP in rescuing chemotaxis could be due to the absence of this I30 region.,
OMIM_DISEASE Neutropenia, severe congenital, X-linked, Wiskott-Aldrich syndrome, Thrombocytopenia, X-linked, Thrombocytopenia, X-linked, intermittent,
SP_COMMENT disease:Defects in WAS are a cause of X-linked severe congenital neutropenia (XLN) [MIM:300299]. XLN is an X-linked immunodeficiency syndrome characterized by recurrent major bacterial infections, severe congenital neutropenia, and monocytopenia., disease:Defects in WAS are the cause of thrombocytopenia type 1 (THC1) [MIM:313900]. Thrombocytopenia is defined by a decrease in the number of platelets in circulating blood, resulting in the potential for increased bleeding and decreased ability for clotting., disease:Defects in WAS are the cause of Wiskott-Aldrich syndrome (WAS) [MIM:301000]; also known as eczema-thrombocytopenia-immunodeficiency syndrome. WAS is an X-linked recessive immunodeficiency characterized by eczema, thrombocytopenia, recurrent infections, and bloody diarrhea. Death usually occurs before age 10., domain:The CRIB (Cdc42/Rac-interactive-binding) region binds to the C-terminal WH2 domain in the autoinhibited state of the protein. Binding of Rho-type GTPases to the CRIB induces a conformation change and leads to activation., domain:The WH1 (Wasp homology 1) domain may bind a Pro-rich ligand., function:Effector protein for Rho-type GTPases, providing a link with the Arp2/3 complex that regulates the structure and dynamics of the actin cytoskeleton. Important for efficient actin polymerization. Possible regulator of lymphocyte and platelet function., online information:WAS mutation db, online information:Wiskott-Aldrich syndrome protein entry, similarity:Contains 1 CRIB domain., similarity:Contains 1 WH1 domain., similarity:Contains 1 WH2 domain., subunit:Binds to CDC42, RAC, NCK, FYN, SRC kinase FGR, BTK, ABL, PSTPIP1, WIP, and to the p85 subunit of PLC-gamma. Binds the Arp2/3 complex., tissue specificity:Expressed predominantly in the thymus. Also found, to a much lesser extent, in the spleen.,