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Annals of the New York Academy of... May 2013Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency characterized by microthrombocytopenia, eczema, recurrent infections, and an increased... (Review)
Review
Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency characterized by microthrombocytopenia, eczema, recurrent infections, and an increased incidence of autoimmunity and malignancies. The disease is caused by mutations in the WAS gene expressed exclusively in hematopoietic cells. WAS protein (WASp) is a multidomain protein that exists in complex with several partners that play important roles in its function. WASp belongs to a family of proteins that relay signals from the surface of the cell to the actin cytoskeleton. Mutations in the WAS gene have various effects on the level of WASp, which, in turn, correlates with the severity of the disease. In addition to WAS, mutations in the WAS gene can result in the mild variant X-linked thrombocytopenia, or in X-linked neutropenia, characterized by neutropenia with myelodysplasia. The absence of functional WASp leads to a severe clinical phenotype that can result in death if not diagnosed and treated early in life. The treatment of choice with the best outcome is hematopoietic stem cell transplantation, preferably from a matched related donor.
Topics: Animals; Humans; Mice; Mutation; Wiskott-Aldrich Syndrome
PubMed: 23527602
DOI: 10.1111/nyas.12049 -
British Journal of Haematology May 2019Wiskott Aldrich syndrome (WAS) is a primary immunodeficiency disease resulting in recurrent infections, eczema and microthrombocytopaenia. In its classical form,... (Review)
Review
Wiskott Aldrich syndrome (WAS) is a primary immunodeficiency disease resulting in recurrent infections, eczema and microthrombocytopaenia. In its classical form, significant combined immune deficiency, autoimmune complications and risk of haematological malignancy necessitate early correction with stem cell transplantation or gene therapy. A milder form, X-linked thrombocytopaenia (XLT), shares similar bleeding risk from thrombocytopaenia but is not associated with other significant clinical features and is generally managed conservatively. Here, we detail our approach to the diagnosis and treatment of classical WAS and XLT.
Topics: Autoimmune Diseases; Conservative Treatment; Eczema; Female; Genetic Techniques; Genetic Therapy; Hematopoietic Stem Cell Transplantation; Heterozygote; Humans; Infection Control; Male; Mutation; Risk Factors; Thrombocytopenia; Wiskott-Aldrich Syndrome
PubMed: 30864154
DOI: 10.1111/bjh.15831 -
Current Opinion in Hematology Jan 2008Wiskott-Aldrich syndrome is caused by mutations of the Wiskott-Aldrich syndrome protein gene, which codes for a cytoplasmic protein with multiple functions. This review... (Review)
Review
PURPOSE OF REVIEW
Wiskott-Aldrich syndrome is caused by mutations of the Wiskott-Aldrich syndrome protein gene, which codes for a cytoplasmic protein with multiple functions. This review will focus on recent progress in understanding the molecular basis of Wiskott-Aldrich syndrome and its ramifications for the cure of this lethal disease.
RECENT FINDINGS
The discovery of the causative gene has revealed a spectrum of clinical phenotypes demonstrating a strong genotype/phenotype correlation. 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. Long-term follow up of patients undergoing hematopoietic stem cell transplantation has led to important modifications of the procedure. Studies of Wiskott-Aldrich syndrome protein-deficient cell lines and wasp-knockout mice have paved the way for possible gene therapy.
SUMMARY
Wiskott-Aldrich syndrome protein gene mutations result in four clinical phenotypes: classic Wiskott-Aldrich syndrome and X-linked thrombocytopenia, intermittent thrombocytopenia and neutropenia. Wiskott-Aldrich syndrome protein is a signaling molecule and instrumental for cognate and innate immunity, cell motility and protection against autoimmune disease. The success of hematopoietic stem cell transplantation is related to the recipient's age, donor selection, the conditioning regimen and the extent of reconstitution. Since Wiskott-Aldrich syndrome protein is expressed exclusively in hematopoietic stem cells, and because Wiskott-Aldrich syndrome protein exerts a strong selective pressure, gene therapy is expected to cure the disease.
Topics: Adult; Animals; Child; Cohort Studies; Disease Models, Animal; Genetic Therapy; Genotype; Hematopoietic Stem Cell Transplantation; Humans; Male; Mice; Mice, Knockout; Neutropenia; Periodicity; Phenotype; Protein Structure, Tertiary; Thrombocytopenia; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein; Wiskott-Aldrich Syndrome Protein Family; X Chromosome
PubMed: 18043243
DOI: 10.1097/MOH.0b013e3282f30448 -
American Journal of Hematology May 2024
Topics: Humans; Wiskott-Aldrich Syndrome
PubMed: 38100131
DOI: 10.1002/ajh.27183 -
Current Allergy and Asthma Reports Sep 2001Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency characterized by thrombocytopenia with small platelets, eczema, recurrent infections, autoimmune... (Review)
Review
Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency characterized by thrombocytopenia with small platelets, eczema, recurrent infections, autoimmune disorders, IgA nephropathy, and an increased incidence of hematopoietic malignancies. The identification of the responsible gene, WASP (Wiskott-Aldrich Syndrome Protein), revealed clinical heterogeneity of the syndrome, and showed that X-linked thrombocytopenia without, or with only mild immunodeficiency and eczema, is also caused by mutations of WASP. The study of WASP and its mutations demonstrates how a single gene defect can cause multiple and complex clinical symptoms.
Topics: Animals; Humans; Immunologic Deficiency Syndromes; Wiskott-Aldrich Syndrome
PubMed: 11892069
DOI: 10.1007/s11882-001-0028-0 -
The Israel Medical Association Journal... May 2002
Review
Topics: Humans; Proteins; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 12040832
DOI: No ID Found -
The Journal of Allergy and Clinical... Apr 2006The Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder with variable clinical phenotypes that correlate with the type of mutations in the WAS protein (WASP)... (Review)
Review
The Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder with variable clinical phenotypes that correlate with the type of mutations in the WAS protein (WASP) gene. WASP, a key regulator of actin polymerization in hematopoietic cells, has 5 well-defined domains that are involved in signaling, cell locomotion, and immune synapse formation. WASP facilitates the nuclear translocation of nuclear factor kappaB and was shown to play an important role in lymphoid development and in the maturation and function of myeloid monocytic cells. Mutations of WASP are located throughout the gene and either inhibit or dysregulate normal WASP function. Analysis of a large patient population demonstrates a phenotype-genotype correlation: classic WAS occurs when WASP is absent, X-linked thrombocytopenia when mutated WASP is expressed, and X-linked neutropenia when missense mutations occur in the Cdc42-binding site. The progress made in dissecting the function of WASP has provided new diagnostic possibilities and has propelled our therapeutic strategies from conservative symptomatic treatment to curative hematopoietic stem cell transplantation and toward gene therapy.
Topics: Actins; Autoimmune Diseases; Cell Communication; Cell Movement; Eczema; Genotype; Humans; Male; Models, Biological; Mutation; Neoplasms; Phenotype; Signal Transduction; Thrombocytopenia; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 16630926
DOI: 10.1016/j.jaci.2006.02.005 -
Expert Review of Clinical Immunology Jun 2022Wiskott-Aldrich syndrome (WAS) serves as the prototype of how variants in a gene, which encodes a protein central to actin cytoskeletal homeostasis can manifest... (Review)
Review
INTRODUCTION
Wiskott-Aldrich syndrome (WAS) serves as the prototype of how variants in a gene, which encodes a protein central to actin cytoskeletal homeostasis can manifest clinically in a variety of ways including infection, atopy, autoimmunity, inflammation, bleeding, neutropenia, non-malignant lymphoproliferation, and malignancy. Despite the discovery of the gene almost 30 years ago, our understanding of the pathophysiological mechanisms underlying WAS continues to unfold.
AREAS COVERED
This review will provide an overview of the approach to the diagnosis of WAS as well as the management of its associated complications. Advances in the use of allogeneic hematopoietic stem cell transplantation (HSCT) and gene therapy as well as the associated challenges unique to WAS will be discussed.
EXPERT OPINION
Basic research, combined with clinical research focusing on longitudinal analysis of WAS patients, will help clarify determinants that influence WAS pathogenesis as well as clinical complications and outcomes. Advances in curative approaches including the use of alternative donor HSCT for WAS continue to evolve. Gene therapy employing safer and more effective protocols ensuring full correction of WAS will provide life-saving benefit to WAS patients who are unable to undergo HSCT.
Topics: Genetic Therapy; Hematopoietic Stem Cell Transplantation; Humans; Neutropenia; Wiskott-Aldrich Syndrome
PubMed: 35533396
DOI: 10.1080/1744666X.2022.2074400 -
Cellular and Molecular Life Sciences :... Sep 2004The Wiskott-Aldrich Syndrome (WAS) is an inherited immunodeficiency caused by a variety of mutations in the gene encoding the WAS protein (WASp). WASp is expressed in... (Review)
Review
The Wiskott-Aldrich Syndrome (WAS) is an inherited immunodeficiency caused by a variety of mutations in the gene encoding the WAS protein (WASp). WASp is expressed in hematopoetic cells and facilitates the reorganization of the actin cytoskeleton in response to many important cell stimuli. Extensive study of WAS and more recently WASp has given great insight into the relevance of this molecule and related molecules to both basic cell biology and human immune defenses.
Topics: Animals; Blood Platelets; Eczema; Genetic Therapy; Humans; Proteins; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 15378206
DOI: 10.1007/s00018-004-4086-z -
Journal of Leukocyte Biology Mar 2018Microthrombocytopenia is the clinical hallmark of WAS, a rare X-linked immunodeficiency that is characterized by eczema, autoimmunity, and cancer susceptibility. This... (Review)
Review
Microthrombocytopenia is the clinical hallmark of WAS, a rare X-linked immunodeficiency that is characterized by eczema, autoimmunity, and cancer susceptibility. This disease is caused by mutations in the WAS gene, which is expressed in hematopoietic cells and regulates actin cytoskeleton remodeling thereby modulating various cellular functions, including motility, immunologic synapse assembly, and signaling. Despite extensive studies that have provided great insight into the relevance of this molecule to innate and cellular immunity, the exact mechanisms of microthrombocytopenia in WAS are still unknown. This review focuses on the recent progress made in dissecting the pathogenesis of platelet defects in patients with WAS and their murine counterparts. In parallel, we will provide an overview of the state-of-the art platelets as immune modulators at the interface between hemostasis and the immune system, which suggests that these cells may have a direct role in the pathogenesis of immune dysregulation in WAS.
Topics: Animals; Autoimmunity; Blood Platelets; Humans; Signal Transduction; Wiskott-Aldrich Syndrome
PubMed: 28851742
DOI: 10.1189/jlb.5MR0617-257R