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Wiskott–Aldrich syndrome

Andrea M Byrne, Tal Schechter, Robyn Westmacott
We report the neuropsychological profile of a 6-year-old girl with Wiskott-Aldrich syndrome, a rare X-linked immunodeficiency disorder associated with thrombocytopenia, eczema, recurrent infections, and malignancy. Wiskott-Aldrich syndrome occurs almost exclusively in males and is extremely rare in females, with no known research focused on cognitive and academic functioning in this population. Our patient was referred due to concerns about her memory and academic functioning. She had a history of progressive thrombocytopenia and hematopoietic stem cell transplantation at age 15 months...
March 2018: Cognitive and Behavioral Neurology: Official Journal of the Society for Behavioral and Cognitive Neurology
Dmitry Balashov, Alexandra Laberko, Anna Shcherbina, Pavel Trakhtman, Dmitrii Abramov, Elena Gutovskaya, Svetlana Kozlovskaya, Larisa Shelikhova, Galina Novichkova, Michael Maschan, Alexander Rumiantsev, Alexei Maschan
Our initial experience of hematopoietic stem cell transplantation (HSCT) from a matched unrelated donor (MUD; n=12) or a haploidentical related donor (n=6) with TCRαβ+/CD19+ graft depletion for Wiskott-Aldrich syndrome (WAS) patients (n=18) showed a dramatic decrease in the incidence of graft-versus-host disease (GVHD) and transplant-related mortality, with an increased rate of overall survival (OS) of 88,9%. Unfortunately, the treatment was associated with mixed myeloid donor chimerism and secondary graft dysfunction (severe thrombocytopenia, n=2; graft rejection, n=5)...
March 14, 2018: Biology of Blood and Marrow Transplantation
Jeffrey M Verboon, Jacob R Decker, Mitsutoshi Nakamura, Susan M Parkhurst
WASH, a Wiskott Aldrich Syndrome (WAS) family protein, has many cell and developmental roles related to its function as a branched actin nucleation factor. Similar to mammalian WASH, which is embryonic lethal, Drosophila Wash was found to be essential for oogenesis and larval development. Recently, however, Drosophila wash was reported to be homozygous viable. Here we verify that the original wash null allele harbors an unrelated lethal background mutation, however, this unrelated lethal mutation does not contribute to any Wash oogenesis phenotypes...
March 16, 2018: Journal of Cell Science
Xiaoyu Sun, Jinzhi Wang, Tao Qin, Yongjie Zhang, Lu Huang, Linlin Niu, Xiaoming Bai, Yukai Jing, Xingtian Xuan, Heather Miller, Yao Zhao, Wenxia Song, Xuemei Tang, Zhiyong Zhang, Xiaodong Zhao, Chaohong Liu
Dock8 deficiency leads to immunodeficiency, and the role of Dock8 in B-cell development and function has been revealed; however, the role of DocK8 on B-cell receptor (BCR) signaling and function of memory B cells remains elusive. In this study, we generated a Dock8 knockout mouse model and collected peripheral blood mononuclear cells from Dock8 patients to study the effect of Dock8 deficiency on the BCR signaling and activation of memory B cells with confocal microscopy and total internal reflection fluorescence microscopy...
February 27, 2018: Blood Advances
Qing Deng, Yan-Xiao Tian, JianJun Liang
Breast tumour progression results from the advancement of the disease to a metastatic phenotype. Rac1 and Cdc42 belong to the Rho family of genes that, together with their downstream effectors, Wiskott-Aldrich Syndrome protein-family verprolin-homologous protein 2 (WAVE2) and Arp2/3, assume a vital part in cytoskeletal rearrangement and the arrangement of film projections that advance malignant cell relocation and invasion. Mangiferin is a characteristic polyphenolic compound from Mangifera indica L. (Anacardiaceae), ordinarily referred to as mango, that is consumed worldwide as a natural product, including culinary and seasoning applications...
February 17, 2018: Cytotechnology
K E Cervantes-Luevano, N Caronni, M C Castiello, E Fontana, G Piperno, A Naseem, P Uva, M Bosticardo, G E Marcovecchio, L D Notarangelo, M P Cicalese, A Aiuti, A Villa, F Benvenuti
BACKGROUND: Wiskott-Aldrich syndrome (WAS) is a rare primary immunodeficiency caused by mutations in WASp, a key regulator of cytoskeletal dynamics in hematopoietic cells. A high proportion of patients develop autoimmunity due to a breakdown in T and B cell tolerance. Moreover, excessive production of type-I interferon by plasmacytoid DCs contribute to autoimmune signs, however, the factors that triggers excessive innate activation have not been defined. OBJECTIVE: Neutrophils extracellular traps (NETs) emerged as major initiating factors in diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA)...
February 12, 2018: Journal of Allergy and Clinical Immunology
Lucia Sereni, Maria Carmina Castiello, Francesco Marangoni, Achille Anselmo, Dario di Silvestre, Sara Motta, Elena Draghici, Stefano Mantero, Adrian J Thrasher, Silvia Giliani, Alessandro Aiuti, Pierluigi Mauri, Luigi D Notarangelo, Marita Bosticardo, Anna Villa
BACKGROUND: Wiskott-Aldrich syndrome (WAS) is an X-linked immunodeficiency characterized by eczema, infections, and susceptibility to autoimmunity and malignancies. Thrombocytopenia is a constant finding, but its pathogenesis remains elusive. OBJECTIVE: To dissect the basis of the WAS platelet defect, we used a novel conditional mouse model (CoWas) lacking Wiskott-Aldrich syndrome protein (WASp) only in the megakaryocytic lineage in the presence of a normal immunologic environment, and in parallel we analyzed samples obtained from patients with WAS...
February 6, 2018: Journal of Allergy and Clinical Immunology
Cesar A López, Clifford J Unkefer, Basil I Swanson, Jessica M J Swanson, S Gnanakaran
Mycolactone is the exotoxin produced by Mycobacterium ulcerans and is the virulence factor behind the neglected tropical disease Buruli ulcer. The toxin has a broad spectrum of biological effects within the host organism, stemming from its interaction with at least two molecular targets and the inhibition of protein uptake into the endoplasmic reticulum. Although it has been shown that the toxin can passively permeate into host cells, it is clearly lipophilic. Association with lipid carriers would have substantial implications for the toxin's distribution within a host organism, delivery to cellular targets, diagnostic susceptibility, and mechanisms of pathogenicity...
February 5, 2018: PLoS Computational Biology
Qing Luan, Alex Zelter, Michael J MacCoss, Trisha N Davis, Brad J Nolen
Arp2/3 complex nucleates branched actin filaments important for cellular motility and endocytosis. WASP family proteins are Arp2/3 complex activators that play multiple roles in branching nucleation, but little is known about the structural bases of these WASP functions, owing to an incomplete understanding of how WASP binds Arp2/3 complex. Recent data show WASP binds two sites, and biochemical and structural studies led to models in which the WASP C segment engages the barbed ends of the Arp3 and Arp2 subunits while the WASP A segment binds the back side of the complex on Arp3...
February 13, 2018: Proceedings of the National Academy of Sciences of the United States of America
Raïssa Houmadi, Delphine Guipouy, Javier Rey-Barroso, Zilton Vasconcelos, Julie Cornet, Manoel Manghi, Nicolas Destainville, Salvatore Valitutti, Sophie Allart, Loïc Dupré
T lymphocyte cytotoxicity relies on a synaptic ring of lymphocyte function-associated antigen 1 (LFA-1), which permits polarized delivery of lytic granules. How LFA-1 organization is controlled by underlying actin cytoskeleton dynamics is poorly understood. Here, we explored the contribution of the actin cytoskeleton regulator WASP to the topography of LFA-1 using a combination of microscopy modalities. We uncover that the reduced cytotoxicity of Wiskott-Aldrich syndrome patient-derived CD8+ T lymphocytes lacking WASP is associated with reduced LFA-1 activation, unstable synapse, and delayed lethal hit...
January 23, 2018: Cell Reports
Christina Mangurian, Wendy Packman, Nicholas S Riano, Julia Kearney
OBJECTIVE: Pediatric bone marrow transplants represent a medically stressful, potentially traumatic experience for children and caregivers, and psychological support for parental caregivers is paramount to their long-term well-being. However, many medical centers do not have protocols in place to sustain caregiver well-being during these distressing experiences. METHOD: We report on a case of a 10-month-old infant with Wiskott Aldrich Syndrome who was hospitalized for bone marrow transplantation...
January 30, 2018: Palliative & Supportive Care
Takashi Ohya, Masakatsu Yanagimachi, Kentaro Iwasawa, Shuichiro Umetsu, Tsuyoshi Sogo, Ayano Inui, Tomoo Fujisawa, Shuichi Ito
AIM: To screen primary immunodeficiency, Wiskott-Aldrich syndrome (WAS), and chronic granulomatous disease (CGD) among children with inflammatory bowel disease (IBD). METHODS: This was a single-center retrospective study. Eighteen children with IBD were investigated. We analyzed their expression of Wiskott-Aldrich syndrome protein (WASP) in lymphocytes and superoxide generation in phagocytes using flow cytometry. When the expression of WASP or superoxide generation was low or absent, we performed genetic analysis to determine the cause of this...
December 28, 2017: World Journal of Gastroenterology: WJG
Ryota Kaneko, Shohei Yamamoto, Naoko Okamoto, Kosuke Akiyama, Ryosuke Matsuno, Daisuke Toyama, Akihiro Hoshino, Kohsuke Imai, Keiichi Isoyama
Wiskott-Aldrich syndrome is a rare X-linked recessive disease resulting from variations in the WAS gene. Wiskott-Aldrich syndrome is sometimes difficult to differentiate from immune thrombocytopenic purpura. A 2-month-old boy was admitted to our hospital for purpura and thrombocytopenia. His mean platelet volume was reported to be normal. Treatment with intravenous immunoglobulins failed to improve the patient's platelet count. Subsequently, an acute cytomegalovirus infection was confirmed by serological testing and antigenemia...
2018: SAGE Open Medical Case Reports
Marianne Burbage, Francesca Gasparrini, Shweta Aggarwal, Mauro Gaya, Johan Arnold, Usha Nair, Michael Way, Andreas Bruckbauer, Facundo D Batista
Wiskott-Aldrich syndrome (WAS) is an immune pathology associated with mutations in WAS protein (WASp) or in WASp interacting protein (WIP). Together with the small GTPase Cdc42 and other effectors, these proteins participate in the remodelling of the actin network downstream of BCR engagement. Here we show that mice lacking the adaptor protein ITSN2, a G-nucleotide exchange factor (GEF) for Cdc42 that also interacts with WASp and WIP, exhibited increased mortality during primary infection, incomplete protection after Flu vaccination, reduced germinal centre formation and impaired antibody responses to vaccination...
January 16, 2018: ELife
A Coppe, L Nogara, M S Pizzuto, A Cani, S Cesaro, R Masetti, F Locatelli, G Te Kronnie, G Basso, S Bortoluzzi, S Bresolin
The WAS gene product is expressed exclusively in the cytoplasm of hematopoietic cells and constitutional genetic abrogation of WASP leads to Wiskott-Aldrich syndrome (WAS). Moreover, mutational activation of WASP has been associated with X-linked neutropenia (XLN). Although studies reported that patients with constitutional WAS mutations affecting functional WASP expression may present Juvenile MyeloMonocytic Lukemia (JMML)-like features, confounding differential diagnosis above all in the co-presence of mutated RAS, an activating somatic mutation of WASP has not been previously described in JMML patients...
January 7, 2018: Human Mutation
Koustav Sarkar, Seong-Su Han, Kuo-Kwang Wen, Hans D Ochs, Loïc Dupré, Michael M Seidman, Yatin M Vyas
BACKGROUND: Wiskott-Aldrich syndrome (WAS), X-linked thrombocytopenia (XLT), and X-linked neutropenia (XLN), caused by WAS mutations affecting WASp expression or activity, manifest in immunodeficiency, autoimmunity, genomic-instability, and lymphoid-cancer. WASp supports filamentous-actin formation in the cytoplasm and gene-transcription in the nucleus. Although the genetic basis for XLT/WAS has been clarified, the relationships between mutant forms of WASp and the diverse features of these disorders remain ill-defined...
December 14, 2017: Journal of Allergy and Clinical Immunology
Maryam Izadi, Dirk Schlobinski, Maria Lahr, Lukas Schwintzer, Britta Qualmann, Michael M Kessels
Local actin filament formation powers the development of the signal-receiving arbor of neurons that underlies neuronal network formation. Yet, little is known about the molecules that drive these processes and may functionally connect them to the transient calcium pulses observed in restricted areas in the forming dendritic arbor. Here we demonstrate that Cordon-Bleu (Cobl)-like, an uncharacterized protein suggested to represent a very distantly related, evolutionary ancestor of the actin nucleator Cobl, despite having only a single G-actin-binding Wiskott-Aldrich syndrome protein Homology 2 (WH2) domain, massively promoted the formation of F-actin-rich membrane ruffles of COS-7 cells and of dendritic branches of neurons...
January 2, 2018: Journal of Cell Biology
Oliver Andres, Katja Henning, Gabriele Strauß, Annerose Pflug, Georgi Manukjan, Harald Schulze
A high proportion of patients with mucocutaneous bleeding diathesis and suspected inherited or acquired platelet disorder remain without diagnosis even after comprehensive laboratory testing. Since flow cytometry allows investigation of resting and activated platelets on the single cell level by requiring only minimal amounts of blood, this method has become an important assay within the diagnostic algorithm, especially in pediatrics. We therefore developed a standardized and modular flow cytometric approach that contributes to clarify impaired platelet function in a rational step-by-step manner...
December 11, 2017: Platelets
Adi Halle-Bikovski, Sophia Fried, Eva Rozentur-Shkop, Guy Biber, Hadassa Shaked, Noah Joseph, Mira Barda-Saad, Jordan H Chill
Wiskott-Aldrich syndrome protein (WASp) is exclusively expressed in hematopoietic cells and responsible for actin-dependent processes, including cellular activation, migration, and invasiveness. The C-terminal domain of WASp-Interacting Protein (WIP) binds to WASp and regulates its activity by shielding it from degradation in a phosphorylation dependent manner as we previously demonstrated. Mutations in the WAS-encoding gene lead to the primary immunodeficiencies Wiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia (XLT)...
January 19, 2018: ACS Chemical Biology
Dhrubajyoti Sharma, Ankur K Jindal, Amit Rawat, Surjit Singh
Primary immunodeficiency disorders (PIDs) are a group of disorders affecting the capability to fight against infection. These include defects in T cells and B cells affecting cell-mediated and humoral immunity, respectively, combined humoral and cell-mediated immunodeficiency, defects in phagocytosis, complement defects, and defects in cytokine or cytokine signalling pathways which are detrimental for immune function. Depending upon the type and severity, age at onset of symptoms can vary from neonatal period to late childhood...
November 2017: Indian Dermatology Online Journal
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