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Current Opinion in Hematology Jul 2005Mutations of the Wiskott-Aldrich syndrome protein can result in highly variable clinical symptoms that affect the hematopoietic/immunologic system. The responsible gene,... (Review)
Review
PURPOSE OF REVIEW
Mutations of the Wiskott-Aldrich syndrome protein can result in highly variable clinical symptoms that affect the hematopoietic/immunologic system. The responsible gene, WASP, has multiple domains, each with unique functions that were only recently fully recognized.
RECENT FINDINGS
Two new comprehensive studies of patients with mutations of the Wiskott-Aldrich syndrome protein unequivocally demonstrated a strong phenotype-genotype correlation; the most predictive variable was the presence or absence of the Wiskott-Aldrich syndrome protein in the lymphoid cells from patients with X-linked thrombocytopenia or Wiskott-Aldrich syndrome, respectively. A third clinical study revealed a high rate (>70%) of autoimmune disorders in patients with classic Wiskott-Aldrich syndrome, possibly caused by immune dysregulation involving both T and B cell defects. In addition, the Wiskott-Aldrich syndrome protein is required for natural killer cell function by participating in the formation of immunologic synapses and facilitating the nuclear translocation of nuclear factor for activated T cell and nuclear factor-kappaB. Finally, the Wiskott-Aldrich syndrome protein was shown to play an important role in lymphoid development and in the maturation and function of myelomonocytic cells.
SUMMARY
The progress made in dissecting the functions of the Wiskott-Aldrich syndrome protein has direct implications for our understanding of the distinct clinical phenotypes (Wiskott-Aldrich syndrome/X-linked thrombocytopenia; intermittent thrombocytopenia; congenital neutropenia), for making diagnostic and prognostic decisions, and for the selection of therapeutic strategies--from conservative symptomatic treatment to curative hematopoietic stem cell transplantation, or, in the future, gene therapy.
Topics: Animals; Dendritic Cells; Humans; Killer Cells, Natural; Monocytes; Proteins; T-Lymphocytes; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 15928485
DOI: 10.1097/01.moh.0000168520.98990.19 -
Journal of Clinical Immunology Jul 2021
Topics: Anti-Inflammatory Agents; Blood Coagulation Factors; Factor VIIa; Hemophilia A; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Infant; Male; Methylprednisolone; Mutation; Mycophenolic Acid; Recombinant Proteins; Vasculitis; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 33660143
DOI: 10.1007/s10875-021-00978-9 -
Journal of Clinical Immunology Aug 2023Wiskott-Aldrich syndrome is an X-linked recessive primary immune-deficiency disorder very rarely reported from black African children. A 12-year old boy with recurrent... (Review)
Review
Wiskott-Aldrich syndrome is an X-linked recessive primary immune-deficiency disorder very rarely reported from black African children. A 12-year old boy with recurrent sinopulmonary and diarrheal infections, eczema, thrombocytopenia, and low platelet volume was found by whole genome sequencing to harbor a predicted pathogenic c.1205dupC (p.Pro403Alafs*92) variant of a mutation in the WAS gene - confirming the diagnosis. This case report summarizes his presentation and management and provides a useful summary of the diagnosis and the responsible novel genetic mutation.
Topics: Male; Child; Humans; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein; Thrombocytopenia; Eczema; Mutation
PubMed: 37052865
DOI: 10.1007/s10875-023-01487-7 -
FASEB Journal : Official Publication of... Feb 2021The Wiskott-Aldrich syndrome (WAS) is a severe recessive X-linked immunodeficiency resulting from loss-of-function mutations in the WAS gene. Mouse is the only mammalian...
The Wiskott-Aldrich syndrome (WAS) is a severe recessive X-linked immunodeficiency resulting from loss-of-function mutations in the WAS gene. Mouse is the only mammalian model used for investigation of WAS pathogenesis. However, the mouse model does not accurately recapitulate WAS clinical phenotypes, thus, limiting its application in WAS clinical research. Herein, we report the generation of WAS knockout (KO) rabbits via embryo co-injection of Cas9 mRNA and a pair of sgRNAs targeting exons 2 and 7. WAS KO rabbits exhibited many symptoms similar to those of WAS patients, including thrombocytopenia, bleeding tendency, infections, and reduced numbers of T cell in the spleen and peripheral blood. The WAS KO rabbit model provides a new valuable tool for preclinical trials of WAS treatment.
Topics: Animals; CRISPR-Cas Systems; Disease Models, Animal; Gene Knockout Techniques; Phenotype; Rabbits; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 33236397
DOI: 10.1096/fj.202002118RR -
Current Opinion in Immunology Oct 2003Wiskott-Aldrich Syndrome (WAS) is an X-linked immunodeficiency characterized by thrombocytopenia with small platelets, eczema, recurrent infections, autoimmune disorders... (Review)
Review
Wiskott-Aldrich Syndrome (WAS) is an X-linked immunodeficiency characterized by thrombocytopenia with small platelets, eczema, recurrent infections, autoimmune disorders and increased incidence of malignancies. Classic WAS, and a milder form, X-linked thrombocytopenia, are caused by mutations of the WAS protein (WASP) gene. Recent investigations have provided evidence that WASP and several related proteins are involved in the reorganization of the actin cytoskeleton by activating Arp2/3-mediated actin polymerization. This function is controlled by the small GTPase Cdc42, which regulates the autoinhibitory loop formation of WASP. In addition, WASP is involved in cytoplasmic signaling via its interaction with a variety of adaptor molecules. Mutation analysis of large cohorts of WAS/X-linked thrombocytopenia patients has provided evidence for a strong correlation between phenotype and genotype.
Topics: Actins; Biological Transport; Genetic Therapy; Humans; Mutation; Proteins; Signal Transduction; Synapses; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 14499269
DOI: 10.1016/s0952-7915(03)00112-2 -
Annual Review of Immunology 1999The Wiskott-Aldrich Syndrome (WAS) is a rare X-linked primary immunodeficiency that is characterized by recurrent infections, hematopoietic malignancies, eczema, and... (Review)
Review
The Wiskott-Aldrich Syndrome (WAS) is a rare X-linked primary immunodeficiency that is characterized by recurrent infections, hematopoietic malignancies, eczema, and thrombocytopenia. A variety of hematopoietic cells are affected by the genetic defect, including lymphocytes, neutrophils, monocytes, and platelets. Early studies noted both signaling and cytoskeletal abnormalities in lymphocytes from WAS patients. Following the identification of WASP, the gene mutated in patients with this syndrome, and the more generally expressed WASP homologue N-WASP, studies have demonstrated that WASP-family molecules associate with numerous signaling molecules known to alter the actin cytoskeleton. WASP/N-WASP may depolymerize actin directly and/or serve as an adaptor or scaffold for these signaling molecules in a complex cascade that regulates the cytoskeleton.
Topics: Animals; Blood Platelets; Chromosome Mapping; Cytoskeleton; GTP Phosphohydrolases; GTP-Binding Proteins; GTPase-Activating Proteins; Humans; Lymphocytes; Mice; Mutation; Nerve Tissue Proteins; Phenotype; Proteins; Signal Transduction; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein; Wiskott-Aldrich Syndrome Protein, Neuronal
PubMed: 10358777
DOI: 10.1146/annurev.immunol.17.1.905 -
Frontiers in Immunology 2023Wiskott-Aldrich syndrome (WAS) is an X-linked recessive primary immunodeficiency disorder characterized by severe eczema, recurrent infections, and... (Review)
Review
BACKGROUND AND AIMS
Wiskott-Aldrich syndrome (WAS) is an X-linked recessive primary immunodeficiency disorder characterized by severe eczema, recurrent infections, and micro-thrombocytopenia. Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative therapeutic option for patients with classic form. The risk of developing post-transplant tumors appears to be higher in patients with WAS than in other inborn errors of immunity (IEIs), but the actual incidence is not well defined, due to the scarcity of published data.
METHODS
Herein, we describe a 10-year-old patient diagnosed with WAS, treated with HSCT in the first year of life, who subsequently developed two rare solid tumors, kaposiform hemangioendothelioma and desmoid tumor. A review of the literature on post-HSCT tumors in WAS patients has been performed.
RESULTS
The patient received diagnosis of classic WAS at the age of 2 months (Zhu score = 3), confirmed by gene sequencing, which detected the nonsense hemizygous c.37C>T (Arg13X) mutation. At 9 months, patient underwent HSCT from a matched unrelated donor with an adequate immune reconstitution, characterized by normal lymphocyte subpopulations and mitogen proliferation tests. Platelet count significantly increased, even though platelet count never reached reference values. A mixed chimerism was also detected, with a residual WASP- population on monocytes (27.3%). The patient developed a kaposiform hemangioendothelioma at the age of 5. A second abdominal tumor was identified, histologically classified as a desmoid tumor when he reached the age of 10 years. Both hematopoietic and solid tumors were identified in long-term WAS survivors after HSCT.
CONCLUSION
Here, we describe the case of a patient with WAS who developed two rare solid tumors after HSCT. An active surveillance program for the risk of tumors is necessary in the long-term follow-up of post-HSCT WAS patients.
Topics: Male; Humans; Infant; Child; Wiskott-Aldrich Syndrome; Fibromatosis, Aggressive; Sarcoma, Kaposi; Hematopoietic Stem Cell Transplantation
PubMed: 37781361
DOI: 10.3389/fimmu.2023.1229674 -
Nature Medicine Jan 2022
Topics: Genetic Therapy; Humans; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 35075290
DOI: 10.1038/s41591-021-01653-7 -
Reviews in Immunogenetics 2000The Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency associated with thrombocytopenia, bloody diarrhea, eczema, recurrent infections, and a high... (Review)
Review
The Wiskott-Aldrich syndrome (WAS) is an X-linked primary immunodeficiency associated with thrombocytopenia, bloody diarrhea, eczema, recurrent infections, and a high incidence of malignancies. X-linked thrombocytopenia (XLT) is a milder form with predominant platelet abnormalities. Both are caused by mutations of the cytoplasmic WAS protein (WASP). To date, mutations of WASP have been identified in over 340 families and consist of missense and nonsense mutations, deletions and insertions, and splice site mutations. There is a striking correlation between phenotype and genotype. The complex gene product of WASP has multiple functional domains that contribute to actin polymerization, cell motility, intracellular signaling, and apoptosis. Understanding the molecular basis of WAS/XLT not only explains the highly variable clinical phenotype, but also affects the medical management of this serious congenital disorder.
Topics: Humans; Molecular Biology; Phosphorylation; Proteins; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 11258421
DOI: No ID Found -
Pathology, Research and Practice Jan 2024As patients continue to suffer from lymphoproliferative and myeloproliferative diseases known as haematopoietic malignancies can affect the bone marrow, blood, lymph... (Review)
Review
As patients continue to suffer from lymphoproliferative and myeloproliferative diseases known as haematopoietic malignancies can affect the bone marrow, blood, lymph nodes, and lymphatic and non-lymphatic organs. Despite advances in the current treatment, there is still a significant challenge for physicians to improve the therapy of HMs. WASp is an important regulator of actin polymerization and the involvement of WASp in transcription is thought to be linked to the DNA damage response and repair. In some studies, severe immunodeficiency and lymphoid malignancy are caused by WASp mutations or the absence of WASp and these mutations in WAS can alter the function and/or expression of the intracellular protein. Loss-of-function and Gain-of-function mutations in WASp have an impact on cancer malignancies' incidence and onset. Recent studies suggest that depending on the clinical or experimental situation, WASPs and WAVEs can operate as a suppressor or enhancers for cancer malignancy. These dual functions of WASPs and WAVEs in cancer likely arose from their multifaceted role in cells that could be targeted for anticancer drug development. The significant role and their association of WASp in Chronic myeloid leukaemia, Juvenile myelomonocytic leukaemia and T-cell lymphoma is discussed. In this review, we described the structure and function of WASp and its family mechanism, analysing major regulatory effectors and summarising the clinical relevance and drugs that specifically target WASp in disease treatment in various hematopoietic malignancies by different approaches.
Topics: Humans; Wiskott-Aldrich Syndrome Protein; Wiskott-Aldrich Syndrome; Hematologic Neoplasms; Neoplasms; Molecular Biology; Actins
PubMed: 38118219
DOI: 10.1016/j.prp.2023.155026