Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Taking over the Atlas
Dear Colleagues,
The Atlas, once more, is in great danger, and I will have to proceed to a collective economic lay-off of all the team involved in the Atlas before the begining of April 2015 (a foundation having suddenly withdrawn its commitment to support the Atlas). I ask you herein if any Scientific Society (a Society of Cytogenetics, of Clinical Genetics, of Hematology, or a Cancer Society, or any other...), any University and/or Hospital, any Charity, or any database would be interested in taking over the Atlas, in whole or in part. If taking charge of the whole lot is too big, a consortium of various actors could be the solution (I am myself trying to find partners). Could you please spread the information, contact the relevant authorities, and find partners.
Survival of the Atlas will be critically dependant upon your ability to find solutions (and urgently!).
Kind regards.
Jean-Loup Huret
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WAS (Wiskott-Aldrich syndrome)


Other namesIMD2
LocusID (NCBI) 7454
Location Xp11.23
Location_base_pair Starts at 48542186 and ends at 48549817 bp from pter ( according to hg19-Feb_2009)  [Mapping]


Description The WAS gene has been mapped to the region Xp11.22-Xp11.3. It has 12 exons spanning 9 kb of genomic DNA.


Description 502 amino acids; 54 kDa; consists of an N-terminal Ena-VASP homology domain 1 (EVH1), a basic domain, a GTPase binding domain (GBD), polyproline domain and the C-terminal domain comprising of a cluster of verprolin homology (V), central (C) and acidic regions (A) (the VCA domain).
Expression WASP is consitutively expressed in all haematopoietic stem-cell-derived lineages, except in mature red blood cells. Neural WASP (N-WASP) and WASP family verprolin homologous protein 1 (WAVE1), WAVE2 and WAVE3 are more widely expressed.
Localisation WASP is located in the cytoplasmic compartment with highest density along the cell membrane.
  Figure 1: WASP and lymphocyte homeostasis. Dependence on WASP for homeostatic regulation varies with cell lineage and stage of maturity. Early stages of B cell development proceed normally in the bone marrow but homeostatic defects of peripheral subpopulations are apparent. The same is true for peripheral T-cells; and in humans with revertant WASP expression confers a survival advantage to these populations. Picture courtesy of Dr Siobhan Burns.
Function WASP family members function as scaffold proteins, transducing a wide range of signals from proteins or membranes to mediate dynamic changes in the actin cytoskeleton. A lack of WASP results in cytoskeletal defects that compromise multiple aspects of normal cellular activity including proliferation, phagocytosis, immune synapse formation, adhesion and directed migration.
WASP function in Haematopoietic system
WASP is expressed by all leukocytes, but dependence on WASP for homeostatic regulation varies with cell lineage and stage of maturity. WASP is required for the development and survival of mature lymphoid cell lineages but myeloid cell lineages that express normal WASP levels show little or no selective advantage.
WASP function in T cells
T cell development appears normal in WAS patients but the circulating lymphocyte number is reduced and progressively declines throughout childhood. There is decreased thymic output and lowered peripheral T cell survival rates. T cell proliferation in response to TCR stimulation is defective in vitro, and the clonal distribution of TCR β -chain families is usually disturbed.
The morphology of WASP-deficient T cells is disturbed with fewer microvillus-like surface projections. They are less able to proliferate in response to various stimuli because WASP is normally recruited to the immunological synapse. In the absence of WASP, the localised assembly of filamentous actin and recruitment of other immunological synapse proteins is impaired in response to TCR stimulation.
WASP function in B cells
WASP-deficient B cells have defective polarisation, spreading, aggregation and migration in response to CXCL13. Marginal Zone B cells are reduced and they fail to migrate in response to sphingosine-1-phosphate, which is crucial for marginal zone homing. This is consistent with a defect in response to polysaccharide antigens. The abnormal regulation of the actin cytoskeleton in B cells may be important for development of autoimmunity.
WASP function in NK cells
In the absence of WASP, NK cell cytotoxicity is impaired as immune synapse formation relies upon actin polymerisation. There is also defective signal transduction and poor intercellular interactions, particularly with dendritic cells.
WASP function in Invariant NKT cells
Invariant NKT (iNKT) cells express both NK- and T-cell receptors; and recognise lipid antigens via the non-classical class I MHC molecule CD1d. They are thought to be important in initial response to infection, protection from autoimmunity and clearance of malignant cells. WAS patients have reduced numbers of iNKT cells which also secrete less cytokine when stimulated.
WASP function in innate immune cells
WASP-deficient myeloid lineage cells have impaired phagocytosis, a process which relies upon quick and regulated de novo actin polymerisation. In addition, monocytes, macrophages, DCs and osteoclasts lack ability to assemble podosomes in the absence of WASP, resulting in severe defects in adhesion and motility. Efficient cell migration also requires interactions involving integrins. In WASP-deficient human and mouse neutrophils, β2 integrin clustering is defective resulting in impaired integrin-dependent functions that range from adhesion and migration to degranulation and activation of the respiratory burst.
Abnormal Treg have been implicated in the onset of autoimmunity in WAS. WASP-deficient Treg cells fail to proliferate normally in response to TCR simulation and their suppressive activity is impaired in vitro. Dysregulation of B cell tolerance is supported by the presence of autoantibodies in WAS patients and in both WASP null and phosphorylation mutant mice.
  Figure 2: WASP protein function in immune cells. WASP is important in regulating the polymerisation of new branched actin filaments and has a role in processes such as phagocytosis, cell motility and signalling. BCR, B cell receptor; NK, natural killer; TCR, T cell receptor. Picture courtesy of Dr Siobhan Burns.


Germinal More than 295 unique mutations have been identified.
158 unique WASP gene mutations had been identified in a cohort of 270 unrelated WAS/XLT families. The most common are missense mutations, followed by splice-site mutations, short deletions, and nonsense mutations. Insertions, complex mutations, and large deletions are less frequent. Most deletions and insertions involve fewer than 10 nucleotides and result in frame shifting and early termination of transcription.
Amino acid substitutions are typically located in exons 1-4. Splice-site mutations occur predominantly in the downstream half of the WASP gene (introns 6-12).
Mutations affecting invariant splice sites may result in multiple splicing products, which often include small amounts of normal WASP cDNA.
Six mutational hotspots, defined as occurring in > 2,5% of the population, have been identified. Three of these hotspots represent point mutations within the coding regions, whereas the other 3 involve splice sites.
Somatic Patients who have missense or splice-site mutations may have residual protein expression and have a less severe clinical phenotype.

Implicated in

Note Mutations of the WASP gene result in 3 distinct phenotypes: Wiskott-Aldrich Syndrome (WAS), X-linked thrombocytopaenia (XLT), and congenital X-linked neutropaenia (XLN).
Entity Wiskott- Aldrich syndrome (WAS)
Note WAS is characterised by low numbers of small platelets, easy bruising and prolonged bleeding, eczema and recurrent infections. It can be complicated by autoimmunity and haematopoietic cell malignancies.
Prognosis Classical WAS has a poor prognosis, but early treatment with haematopoietic stem cell transplant is curative in most patients. Reported median survival in patient with WAS is age 20 years. Death results from infections, bleeding complications, autoimmune diseases, and malignancies. WAS-associated malignancies have a poor prognosis.
Cytogenetics Mutations of the WASP gene that result in absent or truncated protein are more likely to give rise to the classic WAS phenotype. Three of the six hotspot mutations identified (665C>T, IVS8+1 g>n and IVS8+1 to +6 del gtga) have been found to be predominantly WASP-negative and have a high clinical score characteristic for WAS.
Oncogenesis Malignancies are more frequent in adolescents and young adults with the classic WAS phenotype. Most frequent malignancies reported are B cell lymphoma (often Epstein-Barr virus-positive) and leukaemia. Some younger patients may also present with marrow dysplasia.
Entity X-linked thrombocytopaenia (XLT)
Note A milder clinical variant with fewer problems with eczema and minimal immunological disturbances. Incidence of autoimmune disease is less in XLT but has been reported to occur.
Prognosis XLT patients generally have a benign disease course and excellent long-term survival, but they still carry an increased risk for severe disease-related events such as life-threatening infection (especially post splenectomy), severe bleeding, or autoimmunity and cancer.
Cytogenetics The XLT phenotype is generally those with missense or splice-site mutations that allow expression of normal-sized mutated protein, often in reduced quantity. Three of the six hotspot mutations (168C>T; 290 C>N/291 G>N and IVS6+5g>a) have been found consistently in WASP-positive patients.
Oncogenesis The incidence of malignancies in patients of the XLT phenotype is increased, but is lower than that in classic WAS.
Entity X-linked neutropaenia (XLN)
Note A clinically and biologically distinct WASP-associated disorder, results from presence of a cluster of mutations that confer constitutive WASP activation. These mutations have been found to lead to genetic instability through dysregulation of actin polymerisation. Main clinical symptom is neutropaenia which causes a predisposition to bacterial infection, as well as myelodysplasia and other cytopaenias.
Cytogenetics Only four mutations (Leu270Pro, Ser270Pro, Ile276Ser and Ile294Thr) have been reported so far.

External links

HGNC (Hugo)WAS   12731
Entrez_Gene (NCBI)WAS  7454  Wiskott-Aldrich syndrome
GeneCards (Weizmann)WAS
Ensembl hg19 (Hinxton)ENSG00000015285 [Gene_View]  chrX:48542186-48549817 [Contig_View]  WAS [Vega]
Ensembl hg38 (Hinxton)ENSG00000015285 [Gene_View]  chrX:48542186-48549817 [Contig_View]  WAS [Vega]
ICGC DataPortalENSG00000015285
Genatlas (Paris)WAS
SOURCE (Princeton)WAS
Genomic and cartography
GoldenPath hg19 (UCSC)WAS  -     chrX:48542186-48549817 +  Xp11.4-p11.21   [Description]    (hg19-Feb_2009)
GoldenPath hg38 (UCSC)WAS  -     Xp11.4-p11.21   [Description]    (hg38-Dec_2013)
EnsemblWAS - Xp11.4-p11.21 [CytoView hg19]  WAS - Xp11.4-p11.21 [CytoView hg38]
Mapping of homologs : NCBIWAS [Mapview hg19]  WAS [Mapview hg38]
OMIM300299   300392   313900   
Gene and transcription
Genbank (Entrez)BC002961 BC012738 BI910072 CF529565 EU176449
RefSeq transcript (Entrez)NM_000377
RefSeq genomic (Entrez)AC_000155 NC_000023 NC_018934 NG_007877 NT_079573 NW_001842363 NW_004929439
Consensus coding sequences : CCDS (NCBI)WAS
Cluster EST : UnigeneHs.2157 [ NCBI ]
CGAP (NCI)Hs.2157
Alternative Splicing : Fast-db (Paris)GSHG0031516
Alternative Splicing GalleryENSG00000015285
Gene ExpressionWAS [ NCBI-GEO ]     WAS [ SEEK ]   WAS [ MEM ]
SOURCE (Princeton)Expression in : [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
Protein : pattern, domain, 3D structure
UniProt/SwissProtP42768 (Uniprot)
NextProtP42768  [Medical]
With graphics : InterProP42768
Splice isoforms : SwissVarP42768 (Swissvar)
Domaine pattern : Prosite (Expaxy)CRIB (PS50108)    WH1 (PS50229)    WH2 (PS51082)   
Domains : Interpro (EBI)CRIB_dom    PH_like_dom    WASP    WASP_C    WH1/EVH1    WH2_dom   
Related proteins : CluSTrP42768
Domain families : Pfam (Sanger)PBD (PF00786)    WH1 (PF00568)    WH2 (PF02205)   
Domain families : Pfam (NCBI)pfam00786    pfam00568    pfam02205   
Domain families : Smart (EMBL)PBD (SM00285)  WH1 (SM00461)  WH2 (SM00246)  
DMDM Disease mutations7454
Blocks (Seattle)P42768
PDB (SRS)1CEE    1EJ5    1T84    2A3Z    2K42    2OT0   
PDB (PDBSum)1CEE    1EJ5    1T84    2A3Z    2K42    2OT0   
PDB (IMB)1CEE    1EJ5    1T84    2A3Z    2K42    2OT0   
PDB (RSDB)1CEE    1EJ5    1T84    2A3Z    2K42    2OT0   
Human Protein AtlasENSG00000015285
Peptide AtlasP42768
IPIIPI00001545   IPI00641232   
Protein Interaction databases
IntAct (EBI)P42768
Ontologies - Pathways
Ontology : AmiGOactin binding  small GTPase regulator activity  protein binding  cytosol  protein complex assembly  defense response  immune response  blood coagulation  actin polymerization or depolymerization  epidermis development  vesicle membrane  actin cytoskeleton  endosomal transport  actin filament polymerization  actin filament-based movement  Fc-gamma receptor signaling pathway involved in phagocytosis  T cell activation  identical protein binding  innate immune response  regulation of catalytic activity  T cell receptor signaling pathway  extracellular vesicular exosome  positive regulation of Arp2/3 complex-mediated actin nucleation  
Ontology : EGO-EBIactin binding  small GTPase regulator activity  protein binding  cytosol  protein complex assembly  defense response  immune response  blood coagulation  actin polymerization or depolymerization  epidermis development  vesicle membrane  actin cytoskeleton  endosomal transport  actin filament polymerization  actin filament-based movement  Fc-gamma receptor signaling pathway involved in phagocytosis  T cell activation  identical protein binding  innate immune response  regulation of catalytic activity  T cell receptor signaling pathway  extracellular vesicular exosome  positive regulation of Arp2/3 complex-mediated actin nucleation  
Pathways : KEGGChemokine signaling pathway    Adherens junction    Fc gamma R-mediated phagocytosis    Regulation of actin cytoskeleton    Bacterial invasion of epithelial cells    Pathogenic Escherichia coli infection    Shigellosis    Salmonella infection   
REACTOMEP42768 [protein]
REACTOME PathwaysREACT_6900 Immune System [pathway]
Protein Interaction DatabaseWAS
DoCM (Curated mutations)WAS
Wikipedia pathwaysWAS
Gene fusion - rearrangements
Polymorphisms : SNP, variants
NCBI Variation ViewerWAS [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)WAS
Exome Variant ServerWAS
Genetic variants : HAPMAPWAS
Genomic Variants (DGV)WAS [DGVbeta]
ICGC Data PortalENSG00000015285 
Somatic Mutations in Cancer : COSMICWAS 
CONAN: Copy Number AnalysisWAS 
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
LOVD (Leiden Open Variation Database)**PUBLIC** CCHMC Molecular Genetics Laboratory Mutation Database
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] 
DECIPHER (Syndromes)X:48542186-48549817
Mutations and Diseases : HGMDWAS
OMIM300299    300392    313900   
NextProtP42768 [Medical]
Disease Genetic AssociationWAS
Huge Navigator WAS [HugePedia]  WAS [HugeCancerGEM]
snp3D : Map Gene to Disease7454
DGIdb (Drug Gene Interaction db)WAS
General knowledge
Homologs : HomoloGeneWAS
Homology/Alignments : Family Browser (UCSC)WAS
Phylogenetic Trees/Animal Genes : TreeFamWAS
Chemical/Protein Interactions : CTD7454
Chemical/Pharm GKB GenePA37342
Clinical trialWAS
Cancer Resource (Charite)ENSG00000015285
Other databases
PubMed190 Pubmed reference(s) in Entrez


The Wiskott-Aldrich syndrome.
Ochs HD, Thrasher AJ.
J Allergy Clin Immunol. 2006 Apr;117(4):725-38; quiz 739. (REVIEW)
PMID 16630926
Wiskott-Aldrich Syndrome: Immunodeficiency resulting from defective cell migration and impaired immunostimulatory activation.
Bouma G, Burns SO, Thrasher AJ.
Immunobiology. 2009;214(9-10):778-90. Epub 2009 Jul 22. (REVIEW)
PMID 19628299
Wiskott-Aldrich syndrome: diagnosis, clinical and laboratory manifestations, and treatment.
Ochs HD, Filipovich AH, Veys P, Cowan MJ, Kapoor N.
Biol Blood Marrow Transplant. 2009 Jan;15(1 Suppl):84-90. (REVIEW)
PMID 19147084
New insights into the biology of Wiskott-Aldrich syndrome (WAS).
Thrasher AJ.
Hematology Am Soc Hematol Educ Program. 2009:132-8. (REVIEW)
PMID 20008191
The Wiskott-Aldrich syndrome: The actin cytoskeleton and immune cell function.
Blundell MP, Worth A, Bouma G, Thrasher AJ.
Dis Markers. 2010;29(3-4):157-75. (REVIEW)
PMID 21178275
WASP: a key immunological multitasker.
Thrasher AJ, Burns SO.
Nat Rev Immunol. 2010 Mar;10(3):182-92. (REVIEW)
PMID 20182458
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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Written07-2012Winnie Ip, Siobhan Burns, Adrian Thrasher
Molecular Immunology Unit, Centre for Immunodeficiency, UCL Institute of Child Health, 30 Guilford Street, London, WC1N 1EH, UK


This paper should be referenced as such :
Ip, W ; Burns, S ; Thrasher, A
WAS (Wiskott-Aldrich syndrome)
Atlas Genet Cytogenet Oncol Haematol. 2013;17(2):102-105.
Free journal version : [ pdf ]   [ DOI ]

© Atlas of Genetics and Cytogenetics in Oncology and Haematology
indexed on : Tue Feb 17 20:34:04 CET 2015

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