Wiskott-Aldrich Syndrome

2021 ◽  
Author(s):  
Saeed Sepehrnia
Keyword(s):  
Molecular Basis ◽  
Hematopoietic Cell Transplantation ◽  
Diagnostic Tools ◽  
Missense Mutations ◽  
Primary Immunodeficiency Disorder ◽  
Wiskott Aldrich Syndrome ◽  
Immunodeficiency Disorder ◽  
Wide Range ◽  
Clinical Disorders ◽  
Syndrome Protein

The Wiskott-Aldrich syndrome (WAS) could be a rare X-linked primary immunodeficiency disorder characterized by recurrent infections, eczema, and bleeding following thrombocytopenia. Despite the rarity of this syndrome, today our understanding of the cellular and molecular basis of the pathogenesis of this disease has increased and it’s well established that this disorder encompasses a wide range of clinical disorders including immunodeficiency, atopy, autoimmunity, and cancer. Wiskott–Aldrich Syndrome protein (WASP) mutations are located throughout the gene and inhibit or regulate the conventional function of WASP. Thus classic WAS occurs when WASP is absent, X-linked thrombocytopenia when mutated WASP is expressed, and X-linked neutropenia when missense mutations occur within the Cdc42-binding site. Developments within the use of diagnostic tools, supportive care, and advances in allogeneic hematopoietic cell transplantation have remarkably reduced the mortality related to this disorder. Besides, gene therapy has provided optimistic perspectives on the treatment approaches of those patients.

Cdc42, Rac1, and the Wiskott-Aldrich syndrome protein are involved in the cytoskeletal regulation of B lymphocytes

Blood ◽  
2001 ◽  
Vol 98 (4) ◽  
pp. 1086-1094 ◽  
Author(s):  
Lisa Westerberg ◽  
Gediminas Greicius ◽  
Scott B. Snapper ◽  
Pontus Aspenström ◽  
Eva Severinson
Keyword(s):  
B Cells ◽  
B Lymphocytes ◽  
Interleukin 4 ◽  
Wiskott Aldrich Syndrome ◽  
Cytoskeletal Regulation ◽  
Immunodeficiency Disorder ◽  
Syndrome Protein ◽  
Dependent Processes ◽  
Signal Mediators ◽  
Activated B Cells

Patients with the immunodeficiency disorder Wiskott-Aldrich syndrome (WAS) have lymphocytes with aberrant microvilli, and their T cells, macrophages, and dendritic cells are impaired in cytoskeletal-dependent processes. WAS is caused by a defective or a missing WAS protein (WASP). Signal mediators interleukin-4 (IL-4) and CD40 are important for actin-dependent morphology changes in B cells. A possible function of WASP and its interacting partners, Cdc42 and Rac1, was investigated for these changes. It was found that active Cdc42 and Rac1 induced filopodia and lamellipodia, respectively, in activated B cells. Evidence is given that IL-4 has a specific role in the regulated cycling of Cdc42 because IL-4 partially and transiently depleted active Cdc42 from detergent extract of activated B cells. WASP-deficient B lymphocytes were impaired in IL-4– and CD40-dependent induction of polarized and spread cells. Microvilli were expressed on WASP-deficient B cells, but they appeared shorter and less dense in cell contacts than in wild-type cells. In conclusion, evidence is provided for the involvement of Cdc42, Rac1, and WASP in the cytoskeletal regulation of B lymphocytes. Aberrations in WASP-deficient B lymphocytes, described here, provide further evidence that WAS is a cytoskeletal disease of hematopoietic cells.

scholarly journals Mutational screening of WASP gene in patients with Wiskott-Aldrich syndrome

2021 ◽  
Vol 19 (1) ◽  
pp. 61-68
Author(s):  
Luong Thi Lan Anh ◽  
Nguyen Thanh Hoa ◽  
Nguyen Hai Ha ◽  
Dang Ton Nguyen
Keyword(s):  
Viral Infections ◽  
Clinical Symptoms ◽  
Data Set ◽  
Wiskott Aldrich Syndrome ◽  
Immunodeficiency Disorder ◽  
Increased Risk ◽  
Wasp Gene ◽  
Families With Children ◽  
Syndrome Protein ◽  
Flanking Regions

The Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive immunodeficiency disorder characterized by thrombocytopenia and small-sized platelets, eczema, recurrent bacterial and viral infections, higher incidence of autoimmunity and an increased risk of malignancies. WAS occurs due to the mutation or loss of Wiskott-Aldrich Syndrome Protein (WASP) gene located on Xp11.22 – p11.23 of the short arm of the X chromosome. The absence of functional WASP leads to severe clinical symptoms that results in the deaths of patients if they are not diagnosed and treated early. The objective of the study was to identify mutations in the WASP gene of families with children diagnosed with WAS.The whole coding sequence and the intron-exon flanking regions of the WASP were sequenced by Sanger method. Two cases of children who has WAS were found tocarrymutations in the WASP gene. A c.702insAC mutation leadeda frameshift at position of codon 236 and terminated the protein at the position of codon 262 was identified in patient WA007 and a c.91G>A mutation that transformed glutamic acid to lysineat codon 31 was determined in patient WA010.This study provides a data set and screening of mutations in theWASP gene inVietnamese patientsto further identify the genetic causes and contribute to the clinical management and genetic counseling for the affected families.

scholarly journals WASp is required for the correct temporal morphogenesis of rhabdomere microvilli

2004 ◽  
Vol 164 (3) ◽  
pp. 417-426 ◽  
Author(s):  
Andrew C. Zelhof ◽  
Robert W. Hardy
Keyword(s):  
Drosophila Melanogaster ◽  
Brush Border ◽  
Molecular Basis ◽  
Apical Surface ◽  
Wiskott Aldrich Syndrome ◽  
Syndrome Protein

Microvilli are actin-based fingerlike membrane projections that form the basis of the brush border of enterocytes and the Drosophila melanogaster photoreceptor rhabdomere. Although many microvillar cytoskeletal components have been identified, the molecular basis of microvillus formation is largely undefined. Here, we report that the Wiskott-Aldrich syndrome protein (WASp) is necessary for rhabdomere microvillus morphogenesis. We show that WASp accumulates on the photoreceptor apical surface before microvillus formation, and at the time of microvillus initiation WASp colocalizes with amphiphysin and moesin. The loss of WASp delays the enrichment of F-actin on the apical photoreceptor surface, delays the appearance of the primordial microvillar projections, and subsequently leads to malformed rhabdomeres.

scholarly journals The Wiskott-Aldrich Syndrome: The Actin Cytoskeleton and Immune Cell Function

2010 ◽  
Vol 29 (3-4) ◽  
pp. 157-175 ◽  
Author(s):  
Michael P. Blundell ◽  
Austen Worth ◽  
Gerben Bouma ◽  
Adrian J. Thrasher
Keyword(s):  
Actin Cytoskeleton ◽  
Synapse Formation ◽  
Cell Function ◽  
Immune Cell ◽  
Severe Disease ◽  
Missense Mutations ◽  
Immune Synapse ◽  
Wiskott Aldrich Syndrome ◽  
Activating Mutations ◽  
Syndrome Protein

Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive primary immunodeficiency characterised by immune dysregulation, microthrombocytopaenia, eczema and lymphoid malignancies. Mutations in the WAS gene can lead to distinct syndrome variations which largely, although not exclusively, depend upon the mutation. Premature termination and deletions abrogate Wiskott-Aldrich syndrome protein (WASp) expression and lead to severe disease (WAS). Missense mutations usually result in reduced protein expression and the phenotypically milder X-linked thrombocytopenia (XLT) or attenuated WAS [1-3]. More recently however novel activating mutations have been described that give rise to X-linked neutropenia (XLN), a third syndrome defined by neutropenia with variable myelodysplasia [4-6]. WASP is key in transducing signals from the cell surface to the actin cytoskeleton, and 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.

Mutation Spectrum in Patients with Wiskott-Aldrich Syndrome and X-linked Thrombocytopenia: Identification of Twelve Different Mutations in the WASP Gene

1996 ◽  
Vol 75 (04) ◽  
pp. 546-550 ◽  
Author(s):  
Marianne Schwartz ◽  
Albert Békássy ◽  
Mikael Donnér ◽  
Thomas Hertel ◽  
Stefan Hreidarson ◽  
...  
Keyword(s):  
Base Pair ◽  
Hot Spot ◽  
Missense Mutations ◽  
Nucleotide Substitutions ◽  
Exon 2 ◽  
Wiskott Aldrich Syndrome ◽  
Base Pair Deletion ◽  
Reliable Diagnosis ◽  
Wasp Gene ◽  
Detection Of Mutations

SummaryTwelve different mutations in the WASP gene were found in twelve unrelated families with Wiskott-Aldrich syndrome (WAS) or X-linked thrombocytopenia (XLT). Four frameshift, one splice, one nonsense mutation, and one 18-base-pair deletion were detected in seven patients with WAS. Only missense mutations were found in five patients diagnosed as having XLT. One of the nucleotide substitutions in exon 2 (codon 86) results in an Arg to Cys replacement. Two other nucleotide substitutions in this codon, R86L and R86H, have been reported previously, both giving rise to typical WAS symptoms, indicating a mutational hot spot in this codon. The finding of mutations in the WASP gene in both WAS and XLT gives further evidence of these syndromes being allelic. The relatively small size of the WASP gene facilitates the detection of mutations and a reliable diagnosis of both carriers and affected fetuses in families with WAS or XLT.

scholarly journals The Novel Adaptor Protein, Mti1p, and Vrp1p, a Homolog of Wiskott-Aldrich Syndrome Protein-Interacting Protein (WIP), May Antagonistically Regulate Type I Myosins in Saccharomyces cerevisiae

Genetics ◽  
2002 ◽  
Vol 160 (3) ◽  
pp. 923-934
Author(s):  
Junko Mochida ◽  
Takaharu Yamamoto ◽  
Konomi Fujimura-Kamada ◽  
Kazuma Tanaka
Keyword(s):  
Adaptor Protein ◽  
Actin Binding ◽  
Temperature Sensitive ◽  
Null Mutation ◽  
Type I ◽  
Cortical Actin ◽  
Tail Region ◽  
Interacting Protein ◽  
Wiskott Aldrich Syndrome ◽  
Syndrome Protein

Abstract Type I myosins in yeast, Myo3p and Myo5p (Myo3/5p), are involved in the reorganization of the actin cytoskeleton. The SH3 domain of Myo5p regulates the polymerization of actin through interactions with both Las17p, a homolog of mammalian Wiskott-Aldrich syndrome protein (WASP), and Vrp1p, a homolog of WASP-interacting protein (WIP). Vrp1p is required for both the localization of Myo5p to cortical patch-like structures and the ATP-independent interaction between the Myo5p tail region and actin filaments. We have identified and characterized a new adaptor protein, Mti1p (Myosin tail region-interacting protein), which interacts with the SH3 domains of Myo3/5p. Mti1p co-immunoprecipitated with Myo5p and Mti1p-GFP co-localized with cortical actin patches. A null mutation of MTI1 exhibited synthetic lethal phenotypes with mutations in SAC6 and SLA2, which encode actin-bundling and cortical actin-binding proteins, respectively. Although the mti1 null mutation alone did not display any obvious phenotype, it suppressed vrp1 mutation phenotypes, including temperature-sensitive growth, abnormally large cell morphology, defects in endocytosis and salt-sensitive growth. These results suggest that Mti1p and Vrp1p antagonistically regulate type I myosin functions.

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