Alternative titles; symbols
HGNC Approved Gene Symbol: WAS
SNOMEDCT: 36070007, 718882006; ICD10CM: D82.0; ICD9CM: 279.12;
Cytogenetic location: Xp11.23 Genomic coordinates (GRCh38) : X:48,676,636-48,691,427 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xp11.23 | Neutropenia, severe congenital, X-linked | 300299 | X-linked recessive | 3 |
| Thrombocytopenia, X-linked | 313900 | X-linked recessive | 3 | |
| Thrombocytopenia, X-linked, intermittent | 313900 | X-linked recessive | 3 | |
| Wiskott-Aldrich syndrome | 301000 | X-linked recessive | 3 |
Studies of the Wiskott-Aldrich syndrome (WAS; 301000) led to the characterization and mapping of the WAS gene. To isolate the WAS gene, Derry et al. (1994) used a positional cloning strategy that involved the construction of a clone contig in the critical WAS region Xp11.23-p11.22, bounded by the markers DXS255 and TIMP, Evaluation of several candidate cDNAs led to the identification of a sequence whose expression was limited to lymphocytic and megakaryocytic cell lineages and which was altered in patients with Wiskott-Aldrich syndrome. Derry et al. (1994) referred to the gene as WASP and showed that it encodes a 501-amino acid proline-rich protein. In an erratum, Derry et al. (1994) stated that WASP contains 502 amino acids.
Derry et al. (1995) isolated and sequenced the mouse Wasp gene. The predicted amino acid sequence was found to be 86% identical to the human WASP sequence. The mouse gene is expressed as an mRNA of approximately 2.4 kb in thymus and spleen.
Kwan et al. (1995) updated the coding and genomic sequences of the WAS gene, reporting that it has 12 exons.
Derry et al. (1995) found that a distinctive feature of the mouse Wasp gene is an expanded polymorphic GGA trinucleotide repeat that codes for polyglycine and varies from 15 to 17 triplets in different mouse strains. The genomic structure of the mouse gene closely resembles that in the human with respect to exon/intron positions and intron lengths.
By positional cloning in the critical Wiskott-Aldrich syndrome region at chromosome Xp11.23-p11.22, Derry et al. (1994) identified the WAS gene.
Chromosomal mapping and interspecific backcross performed by Derry et al. (1995) placed the mouse Wasp locus near the centromere of the mouse X chromosome, inseparable from Gata1 (305371), Tcfe3 (314310), and 'scurfy' (sf).
Stewart et al. (1996) used monoclonal anti-WASP antibodies in Western immunoblots to show that WASP is present in the cytoplasmic but not the nuclear fraction of normal human peripheral blood mononuclear cells, platelets, T lymphocytes, non-T lymphocytes, and monocytes. WASP was present in 2 of 4 EBV-transformed cell lines from WAS patients. The failure to find WASP in the nucleus suggested to Stewart et al. (1996) that it is not a transcription factor.
Symons et al. (1996) reported that the Wiskott-Aldrich protein has a GTPase binding site and that it interacts specifically with activated CDC42 (116952), a member of the Rho-like GTPase family. They noted that WASP localizes in the cytoplasm in clusters that are enriched in polymerized actin. They proposed that WASP provides a link between CDC42 and the actin cytoskeleton.
T lymphocytes of males with WAS exhibit a severe disturbance of the actin cytoskeleton, suggesting that the WAS protein may regulate its organization. Kolluri et al. (1996) also showed that WAS protein interacts with CDC42 in a GTP-dependent manner. This interaction was detected in cell lysates, in transient transfections, and with purified recombinant proteins. Different mutant WAS proteins from 3 unrelated affected males retained their ability to interact with Cdc42 but the level of expression of the WAS protein in these mutants was only 2 to 5% of normal. These data suggested to Kolluri et al. (1996) that the WAS protein may function as a signal transduction adaptor downstream of Cdc42 and that, in affected males, the cytoskeletal abnormalities may result from a defect in Cdc42 signaling.
CDC42 can regulate the actin cytoskeleton through activation of WASP family members. Activation relieves an autoinhibitory contact between the GTPase-binding domain and the C-terminal region of WASP proteins. Kim et al. (2000) reported the autoinhibited structure of the GTPase-binding domain of WASP, which can be induced by the C-terminal region or by organic cosolvents. In the autoinhibited complex, intramolecular interactions with the GTPase-binding domain occlude residues of the C terminus that regulate the Arp2/3 actin-nucleating complex (see 604221). Binding of CDC42 to the GTPase-binding domain causes a dramatic conformational change, resulting in disruption of the hydrophobic core and release of the C terminus, enabling its interaction with the actin regulatory machinery.
Using fluorescence anisotropy analysis, Marchand et al. (2001) showed that efficient actin nucleation requires both recruitment of an actin monomer to the ARP2/3 complex and a subsequent activation step. The initial steps in this pathway involve binding by the WA domain of WASP/SCAR (605035) proteins, which consists of a WH2 motif (W) that binds to the actin monomers and an acidic tail (A) that binds to the ARP2/3 complex. Actin filaments seem to stimulate nucleation by enhancing binding of WA to the ARP2/3 complex and favoring the formation of a productive nucleus.
WAS is caused by a mutation in the WAS protein that results in defective actin polymerization. Although the function of many hematopoietic cells requires WAS protein, the specific expression and function of this molecule in natural killer (NK) cells was unknown. Orange et al. (2002) reported that WAS patients had increased percentages of peripheral blood NK cells and that fresh enriched NK cells from 2 patients with a WAS protein mutation had defective cytolytic function. In normal NK cells, WAS protein was expressed and localized to the activating immunologic synapse with filamentous actin (F-actin). Perforin-1 (170280) also localized to the NK cell-activating immunologic synapse, but at a lesser frequency than F-actin and WAS protein. The accumulation of F-actin and WAS protein at the activating immunologic synapse was decreased significantly in NK cells that had been treated with the inhibitor of actin polymerization, cytochalasin D. NK cells from WAS patients lacked expression of WAS protein and accumulated F-actin at the activating immunologic synapse infrequently. Thus, WAS protein has an important function in NK cells. In patients with WAS protein mutations, the resulting NK cell defects are likely to contribute to their disease.
Missense mutations that cause WAS map primarily to the enabled (609061)/VASP (601703) homology-1 (EVH1) domain of WASP. This domain, which is also present in N-WASP (WASL; 605056), has been implicated in both peptide and phospholipid binding. Volkman et al. (2002) showed that the N-WASP EVH1 domain does not bind phosphatidylinositol 4,5-bisphosphate, but it does specifically bind a 25-residue motif from WASP-interacting protein (WIP; 602357). The nuclear magnetic resonance (NMR) structure of the complex revealed a novel recognition mechanism in which the WIP ligand, which is far longer than canonical EVH1 ligands, wraps around the domain, contacting a narrow but extended surface. The authors concluded that this recognition mechanism may provide a basis for understanding the effects of mutations that cause WAS.
Sasahara et al. (2002) showed that the adaptor protein CRKL (602007) binds directly to WIP and that, following T-cell receptor ligation, a CRKL-WIP-WASP complex is recruited by ZAP70 (176947) to lipid rafts and immunologic synapses.
Using mass spectrometric analysis, Scott et al. (2002) identified 25 potential binding partners in a human monocyte cell line for the SH3 domain of HCK (142370). Analysis with purified proteins and in intact cells confirmed the interactions with WIP, WASP, and ELMO1 (606420). Scott et al. (2002) concluded that WIP, WASP, and ELMO1 may be activators or effectors of HCK.
X-Inactivation Status
Wengler et al. (1995) stated that obligate female carriers of the gene for X-linked agammaglobulinemia (300755) show nonrandom X-chromosome inactivation only in B lymphocytes, and obligate female carriers of the gene for X-linked severe combined immunodeficiency (XSCID) show nonrandom X-chromosome inactivation in both T and B lymphocytes, as well as natural killer cells. However, all formed elements of the blood appear to be affected, as a rule, in obligate carriers of WAS, as judged by the criteria of nonrandom X-chromosome inactivation and segregation of G6PD alleles in informative females. Wengler et al. (1995) demonstrated that CD34+ hematopoietic progenitor cells collected from obligate carriers of WAS by apheresis showed nonrandom inactivation. They used PCR analysis of a polymorphic VNTR within the X-linked androgen receptor gene (313700) to demonstrate nonrandom inactivation which clearly must occur early during hematopoietic differentiation.
Parolini et al. (1998) reported X-linked WAS in an 8-year-old girl. She had a sporadic mutation, glu133 to lys, on the paternally derived X chromosome, but had nonrandom X inactivation of the maternal X chromosome in both blood and buccal mucosa. Her mother and maternal grandmother also had nonrandom X inactivation, which suggested to the authors the possibility of a defect in XIST (314670) or some other gene involved in the X-inactivation process. Puck and Willard (1998) commented on the subject of X inactivation in females with X-linked disease in reference to the paper by Parolini et al. (1998).
Reviews
Snapper and Rosen (1999) reviewed the roles of WASP in signaling and cytoskeletal organization.
Cheng et al. (2008) showed that the E. coli EspFU protein binds to the autoinhibitory GTPase binding domain in WASP proteins and displaces it from the activity-bearing VCA domain (for verprolin homology, central hydrophobic, and acidic regions). This interaction potentially activates WASP and neural WASP in vitro and induces localized actin assembly in cells. In the solution structure of the GBD-EspFU complex, EspFU forms an amphipathic helix that binds the GBD, mimicking interactions of the VCA domain in autoinhibited WASP. Thus, EspFU activates WASP by competing directly for the VCA binding site on the GBD. This mechanism is distinct from that used by the eukaryotic activators Cdc42 (116952) and SH2 domains, which globally destabilize the GBD fold to release the VCA. Cheng et al. (2008) suggested that such diversity of mechanisms in WASP proteins is distinct from other multimodular systems, and may result from the intrinsically unstructured nature of the isolated GBD and VCA elements. The structural incompatibility of the GBD complexes with EspFU and Cdc42/SH2, plus high-affinity EspFU binding, enable enterohemorrhagic E. coli to hijack the eukaryotic cytoskeletal machinery effectively.
Mutations in the WAS gene have been found in patients with Wiskott-Aldrich syndrome, X-linked thrombocytopenia (313900), and X-linked severe congenital neutropenia (SCNX; 300299).
Derry et al. (1994) found that the WAS gene was not expressed in 2 unrelated patients with Wiskott-Aldrich syndrome, 1 of whom had a single base deletion that produced a frameshift and premature termination of translation (300392.0001). Two additional patients were identified with point mutations that changed the same arginine residue to either a histidine or a leucine (300392.0002-300392.0003).
In patients with Wiskott-Aldrich syndrome, Kwan et al. (1995) identified 11 additional mutations in the WAS gene that involved single base changes, small deletions, and an insertion. They tabulated 12 mutations in all, located in 6 different exons.
Kolluri et al. (1995) used PCR-SSCP analysis to screen for WAS gene mutations in 19 unrelated boys with the diagnosis of classic or attenuated WAS or isolated thrombocytopenia. All 19 patients had WAS mutations, each of which localized to the initial 3 or terminal 3 exons of the gene, and most of which were unique in each case. However, the arg86-to-his mutation (300392.0003) was found in 1 boy with severe WAS, and an arg86-to-cys mutation was found in 2 boys with severe WAS and 1 boy presenting with thrombocytopenia alone. While the 3 mutations found in isolated thrombocytopenia patients left the reading frame intact, about one-half of the gene alterations detected in both severe and attenuated WAS patients resulted in a frameshift and premature translation termination.
Schindelhauer et al. (1996) found 7 novel and 10 known mutations in the course of mutation analysis in 19 families of German, Swiss, and Turkish descent who presented with WAS and with X-linked thrombocytopenia. They noted a striking clustering of missense mutations in the first 4 exons that contrasted with a random distribution of nonsense mutations. More than 85% of all known missense mutations were located in the amino-terminal stretch of the WAS gene product; this region contained a mutation hotspot at codon 86 (see 300392.0002 and 300392.0003); R86C, R86H, and R86P were observed in this study and R86H was found in 2 unrelated families.
Sequence studies in a WAS patient reported by Stewart et al. (1996) showed a C-to-G transversion at nucleotide position 155 which caused an arginine-to-glycine substitution at codon 41; in a second patient, a C insertion after nucleotide 1016 produced a frameshift resulting in amino acid substitutions at codons 328, 329, 331, and 332. Deletion of a G just after nucleotide 1029 returned the reading frame to normal.
In a study of 16 WAS patients and 4 X-linked thrombocytopenia patients, Thompson et al. (1999) identified 14 distinct mutations, including 7 novel gene defects. Fillat et al. (2001) screened for mutations in the WASP gene using single-strand conformation analysis (SSCA) and sequencing in 14 unrelated Spanish families with 19 affected individuals presenting variable WAS phenotypes. Thirteen mutations (including 9 missense mutations) were identified. Missense mutations were preferentially located in the N-terminal part of the protein (exons 2 and 4), whereas nonsense and frameshift mutations were located in the C-terminal region (exons 10 and 11).
Villa et al. (1995) presented proof that mutations in the WAS gene can result in X-linked thrombocytopenia characterized by thrombocytopenia with small-sized platelets as an isolated finding. Why some mutations impair only the megakaryocytic lineage and have no apparent effect on the lymphoid lineage was unclear. De Saint Basile et al. (1996) also found single point mutations in exon 2 of the WAS gene in 2 unrelated families with a history of isolated X-linked thrombocytopenia.
Devriendt et al. (2001) demonstrated that a constitutively activating mutation in WASP can cause X-linked severe congenital neutropenia; see 300392.0012.
Dobbs et al. (2007) identified 2 different but contiguous single basepair deletions in maternal cousins with WAS (300392.0022 and 300392.0023, respectively). The maternal grandmother was found to be a mosaic for the deletions, both of which occurred on the haplotype from the unaffected maternal great-grandfather, consistent with a bichromatid mutation in a male gamete.
Ancliff et al. (2006) analyzed the WAS gene in 14 boys with severe congenital neutropenia who were negative for mutation in the ELA2 (ELANE; 130130) gene, 8 with classic SCN and 6 with evidence of myelodysplasia and/or immunologic abnormalities in addition to neutropenia, and identified 2 different mutations in 2 probands (S272P, 300392.0024; I294T,300392.0025, respectively).
Beel et al. (2008) analyzed the WAS gene in 60 members of a large Irish kindred segregating X-linked congenital neutropenia, originally reported by Cryan et al. (1988), and identified the I294T mutation in 10 affected males and 8 female carriers.
Humblet-Baron et al. (2007) identified a WAS patient with a history of recurrent autoimmune hemolytic anemia who had a spontaneous revertant mutation in WASP. Previous studies had identified a single-nucleotide deletion in WASP that led to a frameshift, a premature stop codon, and absence of WASP expression. Repeated genetic studies using peripheral blood lymphocytes and a newly derived T-cell line revealed a single-nucleotide insertion at the same genomic site that restored the normal ORF and WASP expression. The reversion was associated with an increase in the relative percentage of WASP-positive/CD4 (186940)-positive/FOXP3 (300292)-positive regulatory T cells (Tregs), as well as clinical improvement manifested by stabilization of red blood cell count and reduction in steroid therapy. Humblet-Baron et al. (2007) concluded that wildtype Tregs expanded in this patient following reversion of a pathogenic WASP mutation, indicating that altered Treg fitness likely explains the autoimmune features in human WAS.
Revertant Mosaicism
Wada et al. (2001) provided evidence that in vivo reversion had occurred in the WAS gene in a patient with Wiskott-Aldrich syndrome, resulting in somatic mosaicism. The mutation was a 6-bp insertion (ACGAGG; 300392.0008) which abrogated expression of the WAS protein. Most of the patient's T lymphocytes expressed nearly normal levels of WAS protein. These lymphocytes were found to lack the deleterious mutation and showed a selective growth advantage in vivo. Analysis of the sequence surrounding the mutation site showed that the 6-bp insertion followed a tandem repeat of the same 6 nucleotides. These findings strongly suggested that DNA polymerase slippage was the cause of the original germline insertion mutation in this family and that the same mechanism was responsible for its deletion in one of the proband's T-cell progenitors, thus leading to reversion mosaicism.
Wada et al. (2004) described 2 additional patients from the same family of the man with revertant T-cell lymphocytes reported by Wada et al. (2001). Somatic mosaicism was demonstrated in leukocytes from the first patient that were cryopreserved when he was 22 years old, 11 years before his death from kidney failure. The second patient, 16 years old at the time of report, had a moderate clinical phenotype and developed revertant cells after the age of 14 years. T lymphocytes showed selective in vivo advantage. These results supported DNA polymerase slippage as a common underlying mechanism and indicated that T-cell mosaicism may have different clinical effects in WAS. Wada et al. (2004) stated that sibs with revertant mosaicism had previously been reported (Wada et al., 2003; Waisfisz et al., 1999), but 3 patients with revertant disease in a single kindred was unprecedented.
Somatic Mosaicism with Second-Site Mutations
Boztug et al. (2008) reported 2 Ukrainian brothers, aged 3 and 4 years, respectively, with WAS due to somatic mosaicism for a truncation mutation and multiple different second-site mutations. Flow cytometric analysis of peripheral blood cells showed that each patient had WAS-negative cells resulting from the truncation mutation and a subset of WAS-positive cells that expressed second-site missense WAS mutations. The second-site mutations resulted in the production of altered, but possibly functional, protein. All second-site mutations in both patients occurred in the same nucleotide triplet in which the truncation mutation occurred. Over time, both boys had a decrease in bleeding diathesis and eczema, and normalization of platelet counts. Boztug et al. (2008) suggested that the second-site mutations may confer a proliferative advantage to the affected cells in these patients.
Du et al. (2006) described somatic mosaicism in a 15-year-old WAS patient due to a second-site mutation in the initiation codon. The patient had a germline single-base deletion (11delG; 300392.0019) in the WASP gene, which resulted in a frameshift and abrogated protein expression. Subsequently, a fraction of T and natural killer (NK) cells expressed a smaller WASP, which bound to its cellular partner WASP-interacting protein (WASPIP; 602357). The T and NK cells were found to have an additional mutation in the initiation codon (1A-T; 300392.0020). The results strongly suggested that the smaller WASP was 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. This appeared to be the first report describing somatic mosaicism due to a second-site mutation in the initiation codon in an inherited disorder.
Derry et al. (1995) described the spectrum of novel mutations in 12 additional unrelated families: missense, nonsense, and frameshift mutations involving 8 of the 12 exons of the gene. Two mutations creating premature termination codons were associated with lack of detectable mRNA on Northern blots. Four amino acid substitutions were found in patients with congenital thrombocytopenia and no clinically evident immune defect. A T-cell line from a WAS patient contained 2 independent DNA alterations, a constitutional frameshift mutation also present in peripheral blood lymphocytes from the patient, and a compensatory splice site mutation unique to the cell line. Although RNA from untransformed cells was not available for analysis, Derry et al. (1995) proposed that the splice site mutation was introduced into the T cell during transformation with HTLV-1 and was then selected for during expansion of the culture. The selection hypothesis implies that a mutant protein lacking the 14 amino acids of exon 8 was produced and conveyed a growth advantage to the cells that carried it. In support of this idea was the observation of nonrandom X-inactivation of circulating lymphocytes in female carriers for WAS, due to selection for cells with the normal X chromosome active. Sites in the first 2 exons of the WAS gene appear to be hotspots for mutation; 20 of 31 unrelated families studied by Kolluri et al. (1995) and Derry et al. (1995) had mutations in exon 1 or exon 2.
Wengler et al. (1995) identified 15 novel mutations in the WAS gene in patients with full-blown Wiskott-Aldrich syndrome. These mutations involved single basepair changes, or small insertions or deletions, all of which resulted in premature stop codon, frameshift with secondary premature stop codon, or splice site defect. Zhu et al. (1995) likewise identified 12 unique mutations distributed throughout the WAS gene. Patients with classic WAS had 'more complex' mutations, resulting in termination codons, frameshifts, and early termination. By contrast, 4 unrelated patients with the X-linked thrombocytopenia phenotype had missense mutations affecting exon 2 (in 3) and a splice site mutation affecting exon 9 (in 1).
Schindelhauer et al. (1996) found no genotype/phenotype correlation emerge after a comparison of the identified mutations with the resulting clinical picture for a classic WAS phenotype. A mild course, reminiscent of X-linked thrombocytopenia, or an attenuated phenotype was more often associated with missense than with the other types of mutations.
Greer et al. (1996) examined the genotypes and phenotypes of 24 patients with WAS and compared them with other known mutations of the WASP gene. They demonstrated clustering of WASP mutations within the 4 most N-terminal exons of the gene and identified arg86 as the most prominent hotspot for WASP mutations. They noted the prominence of missense mutations among patients with milder forms of WAS, while noting that missense mutations also comprise a substantial portion of mutations in patients with severe forms of the disease. Greer et al. (1996) concluded that phenotypes and genotypes of WAS are not well correlated; phenotypic outcome cannot be reliably predicted on the basis of WASP genotype.
Lemahieu et al. (1999) identified 17 WASP gene mutations, 12 of which were novel. All missense mutations were located in exons 1 to 4. Most of the nonsense, frameshift, and splice site mutations were found in exons 6 to 11. Mutations that alter splice sites led to the synthesis of several types of mRNAs, a fraction of which represented the normally spliced product. The presence of normally spliced transcripts was correlated with a milder phenotype. When one such case was studied by Western blot analysis, reduced amounts of normal-sized WASP were present. In other cases as well, a correlation was found between the amount of normal or mutant WASP present and the phenotypes of the affected individuals. No protein was detected in 2 individuals with severe Wiskott-Aldrich syndrome. Reduced levels of a normal-sized WASP with a missense mutation were seen in 2 individuals with X-linked thrombocytopenia. Lemahieu et al. (1999) concluded that mutation analysis at the DNA level is not sufficient for predicting clinical course, and that studies at the transcript and protein levels are needed for a better assessment.
Imai et al. (2004) characterized WASP gene mutations in 50 Japanese patients and analyzed the clinical phenotype and course of each. All patients with missense mutations were WASP-positive, i.e., showed presence of the WASP protein; in contrast, patients with nonsense mutations, large deletions, small deletions, and small insertions were WASP-negative. Patients with splice anomalies were either WASP-positive or WASP-negative. The clinical phenotype of each patient correlated with the presence or absence of WASP. Lack of WASP expression was associated with susceptibility to bacterial, viral, fungal, and Pneumocystis carinii infections and with severe eczema, intestinal hemorrhage, death from intracranial bleeding, and malignancies. Rates for overall survival or survival without intracranial hemorrhage or other serious complications were significantly lower in WASP-negative patients.
Vallee et al. (2024) evaluated 577 individuals with Wiskott-Aldrich syndrome from 63 centers in 26 countries born between 1932 and 2014. The median age at diagnosis was 1.5 years (range, 0-68). Of these patients, 464 (80.4%) were alive at last follow-up, and the median age at last follow-up was 8.9 years (range, 0.3-71.1). This resulted in a total of 6,118 reported patient-years. Overall survival of the cohort, censored at hematopoietic stem cell transplant or gene therapy, was 82% (95% confidence interval (CI) 78-87) at age 15 years and 70% (95% CI 61-80) at 30 years. Vallee et al. (2024) found that those with a missense variant in exon 1 or 2 or the intronic hotspot variant c.559+5G-A (300392.0016) (called class I variants) had a better outcome than those with any other variant (class II variants). Individuals with class I variants had a 15-year odds of survival of 93% (95% CI 89-98) and a 30-year odds of survival of 91% (95% CI 86-97), compared with 71% (95% CI 62-81) and 48% (95% CI 34-68) in patients with class II variants. The cumulative incidence rates of disease-related complications such as severe bleeding (p = 0.007), life-threatening infection (p less than 0.0001), and autoimmunity (p = 0.004) occurred significantly later in patients with a class I variant. The cumulative incidence of malignancy (p = 0.6) was not different between classes I and II. Vallee et al. (2024) concluded that their study quantified the risk for specific disease-related complications and that the class of variant is a biomarker to predict the outcome in patients with WAS.
Derry et al. (1995) stated that Wasp may be a candidate for involvement in 'scurfy,' a T cell-mediated fatal lymphoreticular disease of mice that had previously been proposed as a mouse homolog of Wiskott-Aldrich syndrome (Lyon et al., 1990). Northern analysis of sf tissue samples indicated the presence of Wasp mRNA in liver and skin, presumably as a consequence of lymphocyte infiltration, but no abnormalities in the amount or size of mRNA were identified.
Snapper et al. (1998) found that Wasp -/- mice had normal lymphocyte development and Ig levels and responded well to T-dependent and -independent antigens. However, they had decreased peripheral blood lymphocyte and platelet numbers and developed chronic colitis. Responses to anti-Cd3e (186830) stimulation were impaired in Wasp -/- T cells, whereas Wasp -/- B cells responded normally to anti-Ig.
Humblet-Baron et al. (2007) found that Wasp -/- mice developed early-onset, high-titer autoantibodies. Wasp -/- Tregs failed to compete effectively in vivo and were unable to maintain immunologic tolerance in Treg -/- mice. Flow cytometric analysis demonstrated reduced expression of adhesion molecules and chemokine receptors necessary for nonlymphoid tissue entry in Wasp -/- Tregs, suggesting a defect in peripheral Treg activation. Humblet-Baron et al. (2007) concluded that altered fitness of Tregs may explain the autoimmune features of WAS.
Marangoni et al. (2007) found that Wasp -/- natural Tregs (nTregs) engrafted poorly in immunized mice and failed to proliferate or produce Tgfb (190180). Wasp -/- nTregs also showed reduced suppressor cell function against either wildtype or Wasp -/- effector T cells. Human nTregs from WAS patients showed a similar phenotype. Marangoni et al. (2007) proposed that WASP plays an important role in the activation and suppressor functions of nTregs and that dysfunction or incorrect localization of nTregs may contribute to autoimmunity in WAS patients.
Maillard et al. (2007) demonstrated that Wasp -/- mice have decreased numbers of nTregs in thymus and peripheral organs. Wasp -/- nTregs failed to protect against development of colitis in vivo and failed to home to mesenteric mucosa and peripheral sites upon adoptive transfer into wildtype recipient mice. Wasp -/- nTregs had reduced suppressor function in vitro, which could be restored by preincubation with Il2 (147680) and antigen receptor activation, and they were defective in Il10 (124092) secretion. Maillard et al. (2007) concluded that WASP is critical for nTreg function and that nTreg dysfunction is involved in autoimmunity associated with WASP deficiency.
Using 2 different gene-targeting approaches, Cotta-de-Almeida et al. (2007) generated mouse T lymphocytes lacking both Wasp and N-Wasp. These double-knockout T cells were indistinguishable from wildtype T cells, but T-cell development was markedly altered in double-knockout mice. Flow cytometric analysis demonstrated reduced thymocyte and peripheral T-cell numbers in double-knockout mice. Cotta-de-Almeida et al. (2007) found that the combined activity of Wasp and N-Wasp was important for transition from Cd4/Cd8 double-negative thymocytes to Cd4/Cd8 double-positive thymocytes. In addition, double-knockout mice exhibited decreased migration of single-positive T cells from the thymus. Cotta-de-Almeida et al. (2007) concluded that WASP has a unique role in peripheral T-cell function, but T-cell development depends on the combined activity of WASP and N-WASP.
Westerberg et al. (2010) created mice with mutations in the mouse Wasp gene corresponding to the human leu270-to-pro (L270P; 300392.0012) and ile294-to-thr (I294T; 300392.0025) mutations, which cause X-linked neutropenia (SCNX; 300299). These mutations interfered with normal lymphocyte activation by inducing a marked increase in polymerized actin, decreased cell spreading, and increased apoptosis associated with increased genomic instability.
In a patient with Wiskott-Aldrich syndrome (WAS; 301000) who on Northern blot analysis lacked a visible transcript for WAS, Derry et al. (1994) found deletion of a thymine at nucleotide position 211. The change interrupted the predicted open reading frame and led to a termination signal 16 codons downstream.
In a patient with Wiskott-Aldrich syndrome (WAS; 301000), Derry et al. (1994) found a G-to-T transversion that changed codon 86 from an arginine to a leucine. The mutation was identified in the mother and maternal grandmother.
In a patient with Wiskott-Aldrich syndrome (WAS; 301000), unrelated to the patient with the arg86-to-leu mutation (300392.0002), Derry et al. (1994) identified a G-to-A transition at nucleotide 291 changing the same arginine to a histidine. The patient's mother and maternal grandmother were heterozygous for the mutant allele. In one instance, the normal codon CGC was changed to CTC (leu); in the other instance, it was changed to CAC (his).
Schindelhauer et al. (1996) found extremely variable expression of a disease in a large Swiss family with the R86H mutation of 5 affected males. One died in infancy from infections and 2 were diagnosed as having the classic WAS phenotype. In contrast, 2 brothers had a mild phenotype with survival into adulthood and had children of their own.
In a 7-year-old boy with thrombocytopenia with small-sized platelets (THC1; 313900) diagnosed at 3 months of age, Villa et al. (1995) found a C-to-T transition in exon 2 at nucleotide 201, which was predicted to cause substitution of valine for alanine at codon 56. The patient had never shown eczema or increased susceptibility to infection. The same mutation was found in 1 allele in the mother.
In a 6-year-old boy with a negative family history and thrombocytopenia with small-sized platelets (THC1; 313900) who presented with petechiae at the age of 5 months, Villa et al. (1995) found a C-to-G transversion at nucleotide 741 in exon 7, predicted to lead to substitution of glutamic acid for alanine at codon 236. The mother showed the same mutation in 1 allele. The patient had had mild and transient eczema at 10 months of age but had never shown susceptibility to infections.
In a 9-year-old boy who presented with petechiae at the age of 6 months and was found to have thrombocytopenia with small-sized platelets (THC1; 313900), Villa et al. (1995) found a C insertion in a stretch of 5 cytosines between nucleotides 512 and 516 (in exon 1). The insertion caused a shift in the reading frame after codon 160, leading to a premature termination 8 codons downstream at nucleotides 535-537. The same mutation was detected in 1 allele in the mother. The patient had never developed eczema and showed no unusual susceptibility to infections. A younger brother was also affected.
One of 11 new mutations identified by Kwan et al. (1995) in patients with Wiskott-Aldrich syndrome (WAS; 301000) was a CGA-to-TGA transition in exon 1, resulting in an arg34-to-ter conversion.
One of 11 mutations in patients with Wiskott-Aldrich syndrome (WAS; 301000) identified by Kwan et al. (1995) was a 6-bp insertion (ACGAGG) at nucleotide 434 resulting in the introduction of 2 additional amino acids, asp and glu. The mutation occurred in exon 4.
Wada et al. (2001) described a case of somatic mosaicism for this mutation caused by in vivo reversion. The patient came from a kindred in which 6 males in 4 sibships connected by carrier females had Wiskott-Aldrich syndrome (301000). At the age of 10 months, the proband had encephalitis, and between the ages of 2 and 5 years, he had recurrent bruising, eczema, and recurrent otitis media. At age 5, his platelet count was found to be low. Elective splenectomy corrected the platelet number and size. Shortly after splenectomy, he suffered from pneumococcal meningitis. Frequent upper respiratory and/or ear infections and continued eczema occurred until the age of 12 years when the patient was hospitalized for vasculitic rash, thrombocytopenia, and an illness resembling rheumatoid arthritis with concurrent dysgammaglobulinemia and nephritis. The same year, he developed pneumococcal meningitis and sepsis, which were successfully treated. One month later, another episode of pneumococcal meningitis occurred. At age 16, he developed right mastoiditis. From his 20s to the time of report at age 43, the patient had been relatively well, with complaints of sinusitis responding to antibiotic treatment. A maternal uncle developed petechiae early after birth and died at 6 months of age. His brother had a severe WAS phenotype, including thrombocytopenia, infections, arthritis, and vasculitis, and died of renal failure at the age of 33 years. Two maternal cousins also had severe WAS symptoms; one died from pulmonary hemorrhage at age 2.5 years and the other from lymphoma at age 18 years. Wada et al. (2001) identified the ACGAGG insertion in the WAS gene of the proband. They documented somatic mosaicism in the patient, most of whose T lymphocytes expressed nearly normal levels of WAS protein and were found to lack the deleterious mutation. The sequence surrounding the mutation site showed that the 6-bp insertion followed a tandem repeat of the same 6 nucleotides. These findings strongly suggested that DNA polymerase slippage was the cause of the original germline insertion mutation in this family and that the same mechanism was responsible for its deletion in one of the T-cell progenitors in the proband, thus leading to reversion mosaicism and clinical cure.
In addition to classic Wiskott-Aldrich syndrome on the one hand and isolated thrombocytopenia on the other, some patients with mutations in the WAS gene have atypical or attenuated WAS (301000). In contrast to classic WAS patients, the boys manifested only a mild to moderately severe hemorrhagic diathesis during childhood, had mild or no eczema, and lacked a history of severe recurrent infections. As in classic WAS patients, the boys with attenuated WAS showed variable expression of immune abnormalities and their T cells showed lack of proliferative responses to the periodate mitogen, a finding apparently restricted to, and diagnostic of, WAS (Siminovitch et al., 1995). One of the attenuated or atypical cases of WAS reported by Kolluri et al. (1995) was a 27-year-old man who had easy bruising, epistaxis since infancy, mild eczema, and recurrent pneumonia. Renal failure from the age of 13 years required dialysis. A splenectomy was performed at age 23 years following intracranial hemorrhage. The patient was found to carry a T-to-C transition of nucleotide 278, resulting in a ser82-to-pro substitution in exon 2.
De Saint Basile et al. (1996) described a new mutation in a patient from a family with X-linked thrombocytopenia (THC1; 313900). Exon 2 products showed abnormal migration by single-strand conformational polymorphism analysis. A 168C-T transition produced a thr45-to-met missense mutation with no change in charge.
Ho et al. (2001) found the thr45-to-met mutation in affected members of a large Syrian-Lebanese family with X-linked thrombocytopenia. Five family members had undergone splenectomy with rapid and sustained normalization of their platelet numbers. Ho et al. (2001) pointed out that exon 2 is the most common site for mutations associated with XLT and mild forms of WAS, and the 168C-T transition is the most frequent.
In a patient with Wiskott-Aldrich syndrome (WAS; 301000), Ariga et al. (1998) observed 2 mutations in exon 10 of the WASP gene. One mutation was a 1-bp insertion (A) at nucleotide 1099 or 1100. The other was a 1-base deletion (G) from 5 consecutive Gs at nucleotides 1127 to 1131. On further study it was found that some clones contained only the insertion mutation and the patient's mother and sister, who were both carriers, had only the deletion mutation. It was suggested that the insertion mutation occurred somatically in a hematologic progenitor and was potentially capable of correcting the inherited defect. The proband died at the age of 4 years from intracranial hemorrhage; 2 older brothers who also had Wiskott-Aldrich syndrome died at the ages of 10 months and 47 months. It was uncertain whether the proband's disorder was milder as a result of the second mutation. Spontaneous in vivo reversion to normal of an inherited mutation was reported in a patient with adenosine deaminase deficiency (102700.0026) by Hirschhorn et al. (1996).
In a family in which males showed severe congenital neutropenia in an X-linked recessive pedigree pattern (SCNX; 300299) with affected males in 3 sibships in 3 generations, Devriendt et al. (2001) demonstrated a constitutively activating mutation in WASP: an 843T-C transition causing a leu270-to-pro (L270P) mutation in the WAS gene.
Notarangelo et al. (2002) described 2 families in which affected males had a history of intermittent thrombocytopenia (THC1; 313900) with consistently reduced platelet volume, in the absence of other major clinical features, and carried missense mutations of the WASP gene that allowed substantial protein expression. This observation broadened the spectrum of clinical phenotypes associated with WASP gene defects, and indicated the need for molecular analysis in males with reduced platelet volume, regardless of the platelet number. In 1 family reported by Notarangelo et al. (2002), the index case was that of a 7-year-old boy in whom petechiae developed at 1 month of age. He had mild and transient antecubital eczema in infancy. A diagnosis of idiopathic thrombocytopenia was made at the age of 2 years. He continued to have intermittent petechiae and occasional epistaxis associated with variability in the platelet count, but he had consistently low mean platelet volume. His 4-year-old brother and a 39-year-old maternal uncle also had histories of intermittent petechiae, without other symptoms. In this family a 207C-G nucleotide substitution was found in exon 2 of the WAS gene in all 3 affected males, resulting in a pro58-to-arg (P58R) amino acid change. Heterozygosity for this mutation was detected in the mother of the 2 boys.
In a second family with intermittent thrombocytopenia (WAS; 313900) reported by Notarangelo et al. (2002), a single male was affected, a 7-year-old boy who at the age of 3 years had petechiae and bruises. Clinical history was unremarkable for eczema and infection, and immunoglobulins were normal. Mutation analysis revealed a 1476T-A point mutation in exon 11 of the WAS gene, resulting in an ile481-to-asn (I481N) amino acid substitution. The mother was found to be a carrier of this mutation.
Lutskiy et al. (2002) described a patient with Wiskott-Aldrich syndrome (WAS; 301000) with a large deletion in the Xp11.23 region. The deletion, which totaled 15.8 kb, began downstream of DXS1696 and encompassed 13 kb upstream of WASP and included the distal and proximal promoters and exons 1 through 6. The upstream breakpoint was localized in an Alu element. A 26-bp recombinogenic element was located downstream of the 5-prime breakpoint. A 16-bp sequence just upstream of the 5-prime breakpoint shared close homology with the sequence that spanned the 3-prime breakpoint in intron 6. A heptanucleotide of unknown origin, CAGGGGG, linked the 5-prime and 3-prime breakpoints. Lutskiy et al. (2002) stated that this was the largest deletion identified in a Wiskott-Aldrich syndrome patient. The diagnosis had been made at the age of 3 months when he presented with thrombocytopenia, small platelets, severe eczema, bloody diarrhea, and recurrent otitis media. He received regular immunoglobulin transfusions; at age 2 years, splenectomy was performed and, at age 4, he received a bone marrow transplant from an HLA-matched unrelated donor.
Wiskott-Aldrich Syndrome
In a patient with Wiskott-Aldrich syndrome (301000), Kwan et al. (1995) identified a G-to-A transition at position +5 of intron 6 of the WAS gene.
Using RT-PCR, Zhu et al. (1997) found that the IVS6+5G-A variant resulted in 30% wildtype transcripts, and protein was present on Western blot at 3.5% of wildtype levels.
Jin et al. (2004) identified this variant as a mutational hotspot, present in in 6/227 (2.6%) of the WAS families they studied.
Vallee et al. (2024) catagorized the c.559+5G-A mutation as a class I variant, correlated with a milder phenotype and better outcome. It was present in 22/525 (4.2%) of WAS patients with definitive genetic information.
Thrombocytopenia 1
Inoue et al. (2002) reported what they believed to be the first confirmed instance of X-linked thrombocytopenia (THC1; 313900) in a female. She had the IVS6+5G-A mutation in the WAS gene. Her lymphocytes showed a random pattern of X-chromosome inactivation.
Kwan et al. (1995) described a G-to-A transition at position -1 of intron 6 of the WAS gene in a patient with Wiskott-Aldrich syndrome (WAS; 301000). Lutskiy et al. (2002) studied a 14-month-old girl, a cousin of that patient, who had Wiskott-Aldrich syndrome presenting with thrombocytopenia, small platelets, and immunologic dysfunction. Sequencing of the WAS gene showed that the patient was heterozygous for the splice site mutation previously found in her maternal cousin. Levels of WASP in blood mononuclear cells were 60% of normal. X chromosome inactivation in the patient's blood cells was random, demonstrating that both maternal and paternal active X chromosomes were present. These findings indicated that this patient had a defect in the mechanisms that, in disease-free WAS carriers, lead to preferential survival/proliferation of cells bearing the active wildtype X chromosome.
Andreu et al. (2003) reported an IVS6+2T-G splice site mutation in the WAS gene in a boy with Wiskott-Aldrich syndrome (WAS; 301000). As a consequence of the disruption of the normal splicing process, an abnormally long transcript of 38 nucleotides was generated. Such missplicing was probably due to the activation of a cryptic splice donor site located 38 nucleotides downstream of exon 6. The translation of such aberrant mRNA was predicted to produce a truncated protein with a premature stop at codon 190.
Du et al. (2006) described somatic mosaicism in a 15-year-old Wiskott-Aldrich syndrome (WAS; 301000) patient due to a second-hit mutation in the initiation codon of the WAS gene. The germline mutation was a single-basepair deletion in the WAS cDNA, 11delG, which resulted in a frameshift and abrogated protein expression (Gly4fsTer40). The patient had originally been described by Sasahara et al. (2000). Seven years after chemotherapy for Hodgkin disease, expression of WASP was detected in a fraction of T and NK cells. These WASP-expressing cells had a 1A-T (M1_P5del) mutation in the initiation codon. Du et al. (2006) hypothesized that the second-site mutation in the initiation codon resulted in alternative translation initiation from the second ATG that is located downstream of the germline single-nucleotide deletion. The patient was in complete remission at the time of the report of Du et al. (2006).
For discussion of the somatic 1A-T mutation in the WAS gene that was found in compound heterozygous state in a patient with Wiskott-Aldrich syndrome (WAS; 301000) by Du et al. (2006), see 300392.0019.
In an affected grandson of a female first cousin of the 3 patients described originally by Wiskott (1937) with Wiskott-Aldrich syndrome (WAS; 301000), Binder et al. (2006) found a deletion of 2 nucleotides at positions 73 and 74 in exon 1 (coding sequence, 73-74delAC; the first nucleotide is the A of the ATG translation initiation codon) of the WAS gene. The deletion resulted in a frameshift that starts with amino acid 25; the shifted reading frame was open for another 11 amino acids before it resulted in a stop codon.
In a 15-year-old boy with Wiskott-Aldrich syndrome (WAS; 301000), Dobbs et al. (2007) identified a 1-bp deletion (758delA) in codon 242 of exon 7 of the WAS gene. The proband had 2 affected maternal cousins who were found to have a different but contiguous single basepair deletion, a C deletion in codon 241 of exon 7 (300392.0023). The mother of the proband was heterozygous for the A deletion, whereas her 3 sisters, including the mother of the affected cousins, were heterozygous for the C deletion. Their maternal grandmother was found to be a mosaic for deletions, which both occurred on the haplotype from the unaffected maternal great-grandfather, consistent with a bichromatid mutation in a male gamete.
In a 15-year-old boy with Wiskott-Aldrich syndrome (WAS; 301000), Dobbs et al. (2007) identified a 1-bp deletion (758delA; 300392.0022) in codon 242 of exon 7 of the WAS gene. The proband had 2 affected maternal cousins who were found to have a different but contiguous single basepair deletion, a C deletion in codon 241 of exon 7 (300392.0023). The mother of the proband was heterozygous for the A deletion, whereas her 3 sisters, including the mother of the affected cousins, were heterozygous for the C deletion. Their maternal grandmother was found to be a mosaic for deletions, which both occurred on the haplotype from the unaffected maternal great-grandfather, consistent with a bichromatid mutation in a male gamete.
In a boy with severe congenital neutropenia (SCNX; 300299), Ancliff et al. (2006) identified a T-to-C transition in the WAS gene, resulting in a ser272-to-pro (S272P) substitution in the GTPase-binding domain. The mutation was not detected in 50 controls. His mother, maternal aunt, and maternal grandmother were carriers of the mutation, and all had apparent nonrandom X-inactivation with 98%, 85%, and 79% expression, respectively, of the wildtype allele. Functional analysis revealed that the S272P mutation resulted in increased WAS activity and produced marked abnormalities of cytoskeletal structure and dynamics.
In a boy of Zairian parentage with severe congenital neutropenia (SCNX; 300299), Ancliff et al. (2006) identified a T-to-C transition in the WAS gene, resulting in an ile294-to-thr (I294T) substitution in the GTPase-binding domain. The mutation was not detected in 100 randomly chosen controls or in 100 individuals of African origin. The X-chromosome inactivation pattern of his carrier mother showed a mean ratio of 79%:21% (wildtype:mutant alleles), with no significant differences between the inactivation pattern in purified neutrophils and CD3(+) cells. Functional analysis revealed that the I294T mutation resulted in increased WAS activity and produced marked abnormalities of cytoskeletal structure and dynamics.
In affected males and carrier females from a large Irish kindred segregating X-linked congenital neutropenia, originally reported by Cryan et al. (1988), Beel et al. (2008) identified an 882T-C transition in exon 9 of the WAS gene, resulting in the I294T mutation. Functional analysis confirmed that the I294T mutant is constitutively active toward actin polymerization. Four of 6 female carriers showed random X-chromosome inactivation. Two female carriers showed no consistent pattern of asymmetric X-chromosome inactivation.
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