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Immunological Reviews Nov 2009Cytoskeletal structure and dynamic rearrangement are integrally involved in coupling external stimuli to the orchestrated network of molecular interactions and cellular... (Review)
Review
Cytoskeletal structure and dynamic rearrangement are integrally involved in coupling external stimuli to the orchestrated network of molecular interactions and cellular responses required for T-cell effector function. Members of the Wiskott-Aldrich syndrome protein (WASp) family are now widely recognized as cytoskeletal scaffolding adapters that coordinate the transmission of stimulatory signals to downstream induction of actin remodeling and cytoskeletal-dependent T-cell responses. In this review, we discuss the structural and functional properties of the WASp family members, with an emphasis on the roles of these proteins in the molecular pathways underpinning T-cell activation. The contributions of WASp family proteins and the cytoskeletal reorganization they evoke to expression of specific T-cell effector functions and the implications of such activity to normal immune responses and to the immunologic deficits manifested by Wiskott-Aldrich syndrome patients are also described.
Topics: Animals; Cytoskeletal Proteins; Humans; Immunomodulation; Lymphocyte Activation; Protein Multimerization; Signal Transduction; T-Lymphocytes; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein Family
PubMed: 19909364
DOI: 10.1111/j.1600-065X.2009.00846.x -
Current Opinion in Molecular... Oct 2006Wiskott-Aldrich syndrome (WAS) is a complex primary immunodeficiency disorder associated with microthrombocytopenia, autoinnmunity and susceptibility to malignant... (Review)
Review
Wiskott-Aldrich syndrome (WAS) is a complex primary immunodeficiency disorder associated with microthrombocytopenia, autoinnmunity and susceptibility to malignant lymphoma. At the molecular level, this rare disorder is caused by mutations in the gene encoding the Wiskott-Aldrich syndrome protein (WASP). WASP is a cytosolic adaptor protein mediating the rearrangement of the actin cytoskeleton upon surface receptor signaling. Allogenic hematopoietic stem cell (HSC) transplantation represents a curative approach but remains problematic in light of severe risks and side effects. Recently, HSC gene therapy has emerged as an alternative treatment option. Cumulative preclinical data obtained from WASP-deficient murine models and human cells indicate a marked improvement of the impaired cellular and immunological phenotypes associated with WASP deficiency. The first clinical trial is currently being conducted to assess the feasibility, toxicity, and potential therapeutic benefit of transplanting autologous WASP-reconstituted hematopoietic stem cells.
Topics: Animals; Cytoskeleton; Genetic Therapy; Hematopoietic Stem Cell Transplantation; Hematopoietic Stem Cells; Humans; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 17078381
DOI: No ID Found -
Ergebnisse Der Inneren Medizin Und... 1978
Review
Topics: Adolescent; Adult; Age Factors; Child; Child, Preschool; Eczema; Female; Genetic Counseling; Genotype; Heterozygote; Humans; Infections; Male; Middle Aged; Phenotype; Prenatal Diagnosis; Wiskott-Aldrich Syndrome
PubMed: 361383
DOI: No ID Found -
Current Opinion in Hematology Jan 1999Wiskott-Aldrich syndrome initially was described in 1937 and then again in 1954 as an X-linked disorder associated with thrombocytopenia, eczema, and recurrent... (Review)
Review
Wiskott-Aldrich syndrome initially was described in 1937 and then again in 1954 as an X-linked disorder associated with thrombocytopenia, eczema, and recurrent infections. It remained mysterious how different cell lineages could be affected in this syndrome and, more importantly, how the phenotypic features could be so protean. We now know that the features associated with Wiskott-Aldrich syndrome include dysfunction of nearly all effector arms of the immune system, as well as thrombocytopenia with platelet dysfunction. As a consequence of these abnormalities, children and adults with this syndrome have recurrent bleeding, recurrent and significant infections with common and opportunistic organisms, autoimmune disease, and lymphoreticular malignancies. In 1994, the gene that is defective in Wiskott-Aldrich syndrome was identified and found to be a gene with limited homology to any known gene families. In the past 4 years, much has been learned about the role of this protein in cellular function and T-cell responses specifically. This article reviews some recent clinical findings relevant to Wiskott-Aldrich syndrome, the proposed cellular role of this molecule, its biochemical interactions, and genotype-phenotype considerations.
Topics: Clinical Trials as Topic; Genotype; Humans; Mutation; Phenotype; Proteins; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 9915548
DOI: 10.1097/00062752-199901000-00003 -
The Journal of Allergy and Clinical... Jul 2018
Topics: Child; Child, Preschool; Female; Flow Cytometry; Humans; Infant; Infant, Newborn; Male; Mass Screening; Sensitivity and Specificity; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 29729304
DOI: 10.1016/j.jaci.2018.04.017 -
Immunology Today Dec 1998
Review
Topics: Cell Movement; Humans; Leukocytes; Wiskott-Aldrich Syndrome
PubMed: 9864941
DOI: 10.1016/s0167-5699(98)01350-4 -
Pediatric Blood & Cancer Sep 2015Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia (XLT) are caused by mutations of the WAS gene. The genotype-phenotype association of WAS and XLT have not... (Comparative Study)
Comparative Study
BACKGROUND
Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia (XLT) are caused by mutations of the WAS gene. The genotype-phenotype association of WAS and XLT have not been fully elucidated. Here, we established the largest database of WAS in China to further determine the potential correlation between genotype and phenotype and long-term outcome.
PROCEDURES
We collected clinical data of 81 WAS/XLT patients, analyzed mutations of WAS gene at the genomic DNA and transcriptional/translational levels, and quantified three different patterns of WAS protein (WASp) expression in PBMCs by flow cytometry.
RESULTS
There were 60 unique mutations identified, including 20 novel mutations and eight hotspots, from 75 unrelated families with a total of 81 affected members. Nearly all the patients with XLT had missense mutations and were WASp-positive in the peripheral cells, while only half of the patients with missense mutations exhibited the XLT phenotype and detectable WASp. In contrast, patients with nonsense mutations, deletions, insertions, and complex mutations were WASp-negative and developed the classic WAS phenotype. An equal number of patients with splice anomalies were either WASp-positive or WASp-negative. Long-term survival rates were lower in WASp-negative patients compared to WASp-positive patients.
CONCLUSIONS
The clinical phenotype of classic WAS or milder XLT and long-term outcome are potentially influenced by the effect of these defects on gene transcription and translation. Patients with missense mutations allowing expression of mutated WASp and those with splice anomalies, which result in generation of multiple products, including normal WASp, present the attenuated XLT phenotype and show better prognosis.
Topics: Age of Onset; Child, Preschool; China; DNA Mutational Analysis; Databases, Genetic; Diseases in Twins; Flow Cytometry; Gene Expression Regulation; Genetic Diseases, X-Linked; Genotype; Hematopoietic Stem Cell Transplantation; Humans; Infant; Infant, Newborn; Male; Mutation; Phenotype; Protein Biosynthesis; Survival Rate; Thrombocytopenia; Transcription, Genetic; Treatment Outcome; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 25931402
DOI: 10.1002/pbc.25559 -
Pediatric Blood & Cancer Apr 2022
Topics: Child; Dermatitis Herpetiformis; Family; Humans; Wiskott-Aldrich Syndrome; Wiskott-Aldrich Syndrome Protein
PubMed: 34811870
DOI: 10.1002/pbc.29459 -
Blood Apr 1996
Review
Topics: Blood Cells; Humans; Wiskott-Aldrich Syndrome; X Chromosome
PubMed: 8639877
DOI: No ID Found -
Journal of Pediatric Hematology/oncology Aug 2021Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency disorder that is characterized by a triad of microthrombocytopenia, severe immunodeficiency,...
Wiskott-Aldrich syndrome (WAS) is a rare X-linked primary immunodeficiency disorder that is characterized by a triad of microthrombocytopenia, severe immunodeficiency, and eczema. We report the case of a 7-year-old male patient with chronic thrombocytopenia that was diagnosed as WAS after dilatation of the ascending aorta was noticed. WAS is rare, and it is a disease that requires high suspicion for diagnosis. We recommend periodic echocardiography and magnetic resonance imaging examinations to evaluate aortic aneurysms in children with WAS and that surgical intervention should not be delayed when aneurysm is detected.
Topics: Aorta; Aortic Aneurysm; Child; Humans; Male; Thrombocytopenia; Wiskott-Aldrich Syndrome
PubMed: 32890078
DOI: 10.1097/MPH.0000000000001932