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    Wiskott-Aldrich syndrome that was initially diagnosed as immune thrombocytopenic purpura secondary to a cytomegalovirus infection.
    SAGE Open Med Case Rep 2018 9;6:2050313X17753788. Epub 2018 Jan 9.
    Department of Pediatrics, Showa University Fujigaoka Hospital, Yokohama, Japan.
    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. Read More

    Tuning of in vivo cognate B-T cell interactions by Intersectin 2 is required for effective anti-viral B cell immunity.
    Elife 2018 Jan 16;7. Epub 2018 Jan 16.
    Lymphocyte Biology Laboratory, The Francis Crick Institute, London, United Kingdom.
    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. Read More

    Somatic mutations activating Wiskott-Aldrich syndrome protein concomitant with RAS pathway mutations in juvenile myelomonocytic leukemia patients.
    Hum Mutat 2018 Jan 7. Epub 2018 Jan 7.
    Laboratory of Onco-Hematology, Department of Women's and Children's Health, University of Padova, Padova, Italy.
    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. Although studies reported that patients with constitutional WAS mutations affecting functional WASP expression may present juvenile myelomonocytic leukemia (JMML)-like features, confounding differential diagnosis above all in the copresence of mutated RAS, an activating somatic mutation of WASP has not been previously described in JMML patients. Read More

    Lung transplantation after haematopoietic stem cell transplantation for Wiskott-Aldrich syndrome.
    Eur J Cardiothorac Surg 2017 Dec 21. Epub 2017 Dec 21.
    Department of Thoracic Surgery, Kyoto University, Sakyo-ku, Kyoto, Japan.
    The authors report the first case involving a patient with Wiskott-Aldrich syndrome who underwent single living-donor lobar lung transplantation after haematopoietic stem cell transplantation. Haematopoietic stem cell transplantation was performed at 1 year of age; however, he developed severe pulmonary complications. Although lung transplantation is generally contraindicated in patients with immunodeficiency disease, the patient was able to undergo living-donor lobar lung transplantation because his immunodeficiency and thrombocytopenia were well controlled as a result of haematopoietic stem cell transplantation. Read More

    Hematopoietic cell transplantation in primary immunodeficiency - conventional and emerging indications.
    Expert Rev Clin Immunol 2018 Jan 16:1-12. Epub 2018 Jan 16.
    a Institute of Cellular Medicine , Newcastle University , Newcastle Upon Tyne , UK.
    Introduction: Hematopoietic stem cell transplantation (HSCT) is an established curative treatment for many primary immunodeficiencies. Advances in donor selection, graft manipulation, conditioning and treatment of complications, mean that survival for many conditions is now around 90%. Next generation sequencing is identifying new immunodeficiencies, many of which are treatable with HSCT. Read More

    R-loops cause genomic instability in Wiskott-Aldrich syndrome Thelper lymphocytes.
    J Allergy Clin Immunol 2017 Dec 14. Epub 2017 Dec 14.
    Division of Pediatric Hematology-Oncology, Carver College of Medicine and the Stead Family University of Iowa Children's Hospital, Iowa City, IA 52242. Electronic address:
    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. Read More

    Cobl-like promotes actin filament formation and dendritic branching using only a single WH2 domain.
    J Cell Biol 2018 Jan 12;217(1):211-230. Epub 2017 Dec 12.
    Institute of Biochemistry I, Jena University Hospital/Friedrich-Schiller-University Jena, Jena, Germany
    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. Read More

    Diagnosis of platelet function disorders: A standardized, rational, and modular flow cytometric approach.
    Platelets 2017 Dec 11:1-10. Epub 2017 Dec 11.
    e Institute of Experimental Biomedicine , University Hospital Würzburg , Würzburg , Germany.
    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. Read More

    New Structural Insights into Formation of the Key Actin Regulating WIP-WASp Complex Determined by NMR and Molecular Imaging.
    ACS Chem Biol 2018 Jan 7;13(1):100-109. Epub 2017 Dec 7.
    Department of Chemistry, and ‡Mina and Everard Goodman Faculty of Life Sciences, Bar Ilan University , Ramat Gan, 52900, Israel.
    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). Read More

    Approach to a Child with Primary Immunodeficiency Made Simple.
    Indian Dermatol Online J 2017 Nov-Dec;8(6):391-405
    Allergy Immunology Unit, Advanced Pediatrics Centre, Post Graduate Institute of Medical Education and Research, Chandigarh, India.
    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. Read More

    Wiskott-Aldrich syndrome: Two case reports with a novel mutation.
    Pediatr Hematol Oncol 2017 Aug 4;34(5):286-291. Epub 2017 Dec 4.
    b Yuzuncu Yıl University, School of Medicine, Van , Turkey.
    Background: The Wiskott-Aldrich syndrome (WAS) is X-linked recessive disorder associated with microplatelet thrombocytopenia, eczema, infections, and an increased risk of autoimmunity and lymphoid neoplasia. The originally described features of WAS include susceptibility to infections, microthrombocytopenia, and eczema.

    Aim: In this case report, we present our experience about two cases diagnosed with a new mutation. Read More

    Outcomes after Allogeneic Transplant in Patients with Wiskott-Aldrich Syndrome.
    Biol Blood Marrow Transplant 2017 Nov 28. Epub 2017 Nov 28.
    Center for Cell and Gene Therapy, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas. Electronic address:
    Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder characterized by a triad of immunodeficiency, eczema, and thrombocytopenia. Currently, hematopoietic stem cell transplantation (HSCT) is the most reliable curative treatment with excellent results for patients with HLA-matched family or unrelated donors. However, even after fully myeloablative preparative regimens, mixed donor chimerism is a potential concern. Read More

    Crosstalk between WIP and Rho family GTPases.
    Small GTPases 2017 Nov 26. Epub 2017 Nov 26.
    b Centro de Biología Molecular Severo Ochoa (CSIC-UAM) , 28049 Madrid , Spain.
    Through actin-binding proteins such as the neural Wiskott-Aldrich syndrome protein (N-WASP) and WASP-interacting protein (WIP), the Rho family GTPases RhoA, Rac1 and Cdc42 are major modulators of the cytoskeleton. (N-)WASP and WIP control Rho GTPase activity in various cell types, either by direct WIP/(N-)WASP/Cdc42 or potential WIP/RhoA binding, or through secondary links that regulate GTPase distribution and/or transcription levels. WIP helps to regulate filopodium generation and participates in the Rac1-mediated ruffle formation that determines cell motility. Read More

    Tropomyosin-related kinase C (TrkC) enhances podocyte migration by ERK-mediated WAVE2 activation.
    FASEB J 2017 Nov 21. Epub 2017 Nov 21.
    Medizinische Klinik D, Universitätsklinikum Münster, Muenster, Germany;
    Podocyte malfunction is central to glomerular diseases and is marked by defective podocyte intercellular junctions and actin cytoskeletal dynamics. Podocytes share many morphologic features with neurons, so that similar sets of proteins appear to regulate cell process formation. One such protein is the tropomyosin-related kinase C (TrkC). Read More

    ROS and glutathionylation balance cytoskeletal dynamics in neutrophil extracellular trap formation.
    J Cell Biol 2017 Dec 17;216(12):4073-4090. Epub 2017 Nov 17.
    Institute of Pharmacology, University of Bern, Bern, Switzerland
    The antimicrobial defense activity of neutrophils partly depends on their ability to form neutrophil extracellular traps (NETs), but the underlying mechanism controlling NET formation remains unclear. We demonstrate that inhibiting cytoskeletal dynamics with pharmacological agents or by genetic manipulation prevents the degranulation of neutrophils and mitochondrial DNA release required for NET formation. Wiskott-Aldrich syndrome protein-deficient neutrophils are unable to polymerize actin and exhibit a block in both degranulation and DNA release. Read More

    Wiskott-Aldrich syndrome protein regulates autophagy and inflammasome activity in innate immune cells.
    Nat Commun 2017 Nov 17;8(1):1576. Epub 2017 Nov 17.
    Infection, Immunity and Inflammation Program, Great Ormond Street Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH, UK.
    Dysregulation of autophagy and inflammasome activity contributes to the development of auto-inflammatory diseases. Emerging evidence highlights the importance of the actin cytoskeleton in modulating inflammatory responses. Here we show that deficiency of Wiskott-Aldrich syndrome protein (WASp), which signals to the actin cytoskeleton, modulates autophagy and inflammasome function. Read More

    Disruption of Thrombocyte and T Lymphocyte Development by a Mutation in ARPC1B.
    J Immunol 2017 Dec 10;199(12):4036-4045. Epub 2017 Nov 10.
    Blood Cell Development and Function Program, Fox Chase Cancer Center, Philadelphia, PA 19111;
    Regulation of the actin cytoskeleton is crucial for normal development and function of the immune system, as evidenced by the severe immune abnormalities exhibited by patients bearing inactivating mutations in the Wiskott-Aldrich syndrome protein (WASP), a key regulator of actin dynamics. WASP exerts its effects on actin dynamics through a multisubunit complex termed Arp2/3. Despite the critical role played by Arp2/3 as an effector of WASP-mediated control over actin polymerization, mutations in protein components of the Arp2/3 complex had not previously been identified as a cause of immunodeficiency. Read More

    Secreted gelsolin desensitizes and induces apoptosis of infiltrated lymphocytes in prostate cancer.
    Oncotarget 2017 Sep 23;8(44):77152-77167. Epub 2017 Aug 23.
    Institute of Medicine, Chung-Shan Medical University, Taichung, Taiwan.
    Loss of immunosurveillance is a major cause of cancer progression. Here, we demonstrate that gelsolin, a constituent of ejaculate, induces apoptosis of activated lymphocytes in prostate cancer. Gelsolin was highly expressed in prostate cancer cells, and was associated with tumor progression, recurrence, metastasis, and poor prognosis. Read More

    Clinical Manifestations and Pathophysiological Mechanisms of the Wiskott-Aldrich Syndrome.
    J Clin Immunol 2018 Jan 30;38(1):13-27. Epub 2017 Oct 30.
    Division of Immunology and Allergy, University Hospital of Lausanne, Lausanne, Switzerland.
    The Wiskott-Aldrich syndrome (WAS) is a rare X-linked disorder originally described by Dr. Alfred Wiskott in 1937 and Dr. Robert Aldrich in 1954 as a familial disease characterized by infections, bleeding tendency, and eczema. Read More

    Nuclear Wiskott-Aldrich syndrome protein co-regulates T cell factor 1-mediated transcription in T cells.
    Genome Med 2017 Oct 27;9(1):91. Epub 2017 Oct 27.
    Department of Microbiology Tumor and Cell biology, Karolinska Institutet, Stockholm, 171 77, Sweden.
    Background: The Wiskott-Aldrich syndrome protein (WASp) family of actin-nucleating factors are present in the cytoplasm and in the nucleus. The role of nuclear WASp for T cell development remains incompletely defined.

    Methods: We performed WASp chromatin immunoprecipitation and deep sequencing (ChIP-seq) in thymocytes and spleen CD4+ T cells. Read More

    Cardiac leiomodin2 binds to the sides of actin filaments and regulates the ATPase activity of myosin.
    PLoS One 2017 12;12(10):e0186288. Epub 2017 Oct 12.
    University of Pécs, Medical School, Department of Biophysics, Pécs, Hungary.
    Leiomodin proteins are vertebrate homologues of tropomodulin, having a role in the assembly and maintenance of muscle thin filaments. Leiomodin2 contains an N-terminal tropomodulin homolog fragment including tropomyosin-, and actin-binding sites, and a C-terminal Wiskott-Aldrich syndrome homology 2 actin-binding domain. The cardiac leiomodin2 isoform associates to the pointed end of actin filaments, where it supports the lengthening of thin filaments and competes with tropomodulin. Read More

    BCR-ABL1-induced downregulation of WASP in chronic myeloid leukemia involves epigenetic modification and contributes to malignancy.
    Cell Death Dis 2017 Oct 12;8(10):e3114. Epub 2017 Oct 12.
    Departamento de Imunologia, Instituto de Ciências Biomédicas, Universidade de São Paulo, São Paulo, Brazil.
    Chronic myeloid leukemia (CML) is a myeloproliferative disease caused by the BCR-ABL1 tyrosine kinase (TK). The development of TK inhibitors (TKIs) revolutionized the treatment of CML patients. However, TKIs are not effective to those at advanced phases when amplified BCR-ABL1 levels and increased genomic instability lead to secondary oncogenic modifications. Read More

    Descending aortic aneurysm in Wiskott-Aldrich syndrome: options for repair.
    Asian Cardiovasc Thorac Ann 2017 Nov 12;25(9):635-637. Epub 2017 Oct 12.
    1 5994 Newcastle University , Newcastle-upon-Tyne, UK.
    We report open surgical repair of a previously stented descending thoracic aneurysm in a patient with Wiskott-Aldrich syndrome and a platelet count <10 × 109·L-1. The same patient was described previously in a report of the first endovascular stent in this form of vasculitis. We describe the pre- and intraoperative management, and suggest a change in strategy in this setting. Read More

    Therapeutic Drug Monitoring Simulator for Antibiotic Dosage for Methicillin-Resistant Staphylococcus aureus Sepsis in a Patient with Primary Immunodeficiency on Peritoneal Dialysis.
    J Nippon Med Sch 2017 ;84(4):177-182
    Department of Pediatrics, Nippon Medical School.
    Bacterial infections often cause fatal systemic infections in patients with primary immunodeficiency. To prevent unfortunate results, the selection, dose, and dosage of antibiotics are extremely important. Here, we report a case of Wiskott-Aldrich syndrome in a patient undergoing peritoneal dialysis because of chronic renal failure in whom methicillin-resistant Staphylococcus aureus sepsis developed. Read More

    The actin-related p41ARC subunit contributes to p21-activated kinase-1 (PAK1)-mediated glucose uptake into skeletal muscle cells.
    J Biol Chem 2017 Sep 25. Epub 2017 Sep 25.
    Beckman Research Institute of the City of Hope, United States;
    Defects in translocation of the glucose transporter GLUT4 are associated with peripheral insulin resistance, pre-clinical diabetes, and progression to type 2 diabetes. GLUT4 recruitment to the plasma membrane of skeletal muscle cells requires filamentous (F)-actin remodeling. Insulin signaling in muscle requires p21-activated kinase-1 (PAK1), whose downstream signaling triggers actin remodeling that promotes GLUT4 vesicle translocation and glucose uptake into skeletal muscle cells. Read More

    Expression of N-WASP is regulated by HiF1α through the hypoxia response element in the N-WASP promoter.
    Biochem Biophys Rep 2017 Mar 9;9:13-21. Epub 2016 Nov 9.
    School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, Republic of Singapore.
    Cancer cell migration and invasion involves temporal and spatial regulation of actin cytoskeleton reorganization, which is regulated by the WASP family of proteins such as N-WASP (Neural- Wiskott Aldrich Syndrome Protein). We have previously shown that expression of N-WASP was increased under hypoxic conditions. In order to characterize the regulation of N-WASP expression, we constructed an N-WASP promoter driven GFP reporter construct, N-WASPpro-GFP. Read More

    VCA nanobodies target N-WASp to reduce invadopodium formation and functioning.
    PLoS One 2017 22;12(9):e0185076. Epub 2017 Sep 22.
    Department of Biochemistry, Faculty of Medicine and Health Sciences, Rommelaere Campus, Ghent University, Ghent, Belgium.
    Invasive cancer cells develop small actin-based protrusions called invadopodia, which perform a primordial role in metastasis and extracellular matrix remodelling. Neural Wiskott-Aldrich syndrome protein (N-WASp) is a scaffold protein which can directly bind to actin monomers and Arp2/3 and is a crucial player in the formation of an invadopodium precursor. Expression modulation has pointed to an important role for N-WASp in invadopodium formation but the role of its C-terminal VCA domain in this process remains unknown. Read More

    Defective thymic output in WAS patients is associated with abnormal actin organization.
    Sci Rep 2017 Sep 20;7(1):11978. Epub 2017 Sep 20.
    Chongqing Key Laboratory of Child Infection and Immunity, Department of Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorder, International Science and Technology Cooperation base of Child development and Critical Disorders, Children's Hospital of Chongqing Medical University, Chongqing, 400014, China.
    Wiskott-Aldrich syndrome protein (WASp) is a key regulator of the actin cytoskeleton. Defective T - cell function is a major cause for immune deficiency in Wiskott-Aldrich syndrome (WAS) patients. T cells originate in the bone marrow and develop in the thymus, and then migrate to peripheral tissues. Read More

    Control of actin polymerization via the coincidence of phosphoinositides and high membrane curvature.
    J Cell Biol 2017 Nov 18;216(11):3745-3765. Epub 2017 Sep 18.
    Wellcome Trust/Cancer Research UK Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, England, UK
    The conditional use of actin during clathrin-mediated endocytosis in mammalian cells suggests that the cell controls whether and how actin is used. Using a combination of biochemical reconstitution and mammalian cell culture, we elucidate a mechanism by which the coincidence of PI(4,5)P2 and PI(3)P in a curved vesicle triggers actin polymerization. At clathrin-coated pits, PI(3)P is produced by the INPP4A hydrolysis of PI(3,4)P2, and this is necessary for actin-driven endocytosis. Read More

    Comparison of Zinc Finger Nucleases Versus CRISPR-Specific Nucleases for Genome Editing of the Wiskott-Aldrich Syndrome Locus.
    Hum Gene Ther 2017 Oct 25. Epub 2017 Oct 25.
    1 Centre for Genomics and Oncological Research (GENYO), Pfizer/University of Granada/Andalusian Regional Government , Genomic Medicine Department, Granada, Spain.
    Primary immunodeficiencies, including Wiskott-Aldrich syndrome (WAS), are a main target for genome-editing strategies using specific nucleases (SNs) because a small number of corrected hematopoietic stem cells could cure patients. In this work, we have designed various WAS gene-specific CRISPR/Cas9 systems and compared their efficiency and specificity with homodimeric and heterodimeric WAS-specific zinc finger nucleases (ZFNs), using K-562 cells as a cellular model and plasmid nucleofection or integration-deficient lentiviral vectors (IDLVs) for delivery. The various CRISPR/Cas9 and ZFN SNs showed similar efficiency when using plasmid nucleofection for delivery. Read More

    WASH overexpression enhances cancer stem cell properties and correlates with poor prognosis of esophageal carcinoma.
    Cancer Sci 2017 Dec 26;108(12):2358-2365. Epub 2017 Sep 26.
    Biotherapy Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
    There is increasing evidence that cytoskeleton remodeling is involved in cancer progression. Wiskott-Aldrich syndrome protein (WASP) family represents a key regulator of actin cytoskeleton remodeling. However, the underlying mechanism of the WASP family in cancer progression remains elusive. Read More

    TLR5/7-mediated PI3K activation triggers epithelial-mesenchymal transition of ovarian cancer cells through WAVE3-dependent mesothelin or OCT4/SOX2 expression.
    Oncol Rep 2017 Nov 6;38(5):3167-3176. Epub 2017 Sep 6.
    Department of Anatomy, Inje University College of Medicine, Busan 47392, Republic of Korea.
    Toll-like receptor (TLR)-mediated signaling induces cell migration or invasion in several tumors and various stages of cancer. Interactions of mesothelin, a 40-kDa cell surface glycoprotein, with cancer antigen 125 (CA125) is associated with drug resistance, metastasis, and poor clinical outcome of ovarian cancer patients. In this study, we examined the role of TLR5 and TLR7 in the metastasis of ovarian cancer through the induction of mesothelin/CA125 expression and investigated its underlying mechanism. Read More

    Gene Therapy Approaches to Immunodeficiency.
    Hematol Oncol Clin North Am 2017 Oct 29;31(5):823-834. Epub 2017 Jun 29.
    Infection, Immunity, Inflammation, Molecular and Cellular Immunology Section, University College London, UCL Great Ormond Street Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK. Electronic address:
    Transfer of gene-corrected autologous hematopoietic stem cells in patients with primary immunodeficiencies has emerged as a new therapeutic approach. Patients with various conditions lacking a suitable donor have been treated with retroviral vectors and a gene-addition strategy. Initial promising results were shadowed by the occurrence of malignancies in some of these patients. Read More

    An Evolutionarily Conserved Pathway Essential for Orsay Virus Infection of Caenorhabditis elegans.
    MBio 2017 Sep 5;8(5). Epub 2017 Sep 5.
    Departments of Molecular Microbiology and Pathology & Immunology, Washington University in St. Louis School of Medicine, St. Louis, Missouri, USA
    Many fundamental biological discoveries have been made in Caenorhabditis elegans The discovery of Orsay virus has enabled studies of host-virus interactions in this model organism. To identify host factors critical for Orsay virus infection, we designed a forward genetic screen that utilizes a virally induced green fluorescent protein (GFP) reporter. Following chemical mutagenesis, two Viro (virus induced reporter off) mutants that failed to express GFP were mapped to sid-3, a nonreceptor tyrosine kinase, and B0280. Read More

    Wiskott-Aldrich Syndrome Misdiagnosed as Immune Thrombocytopenic Purpura: A Case Report.
    J Pediatr Hematol Oncol 2017 Aug 30. Epub 2017 Aug 30.
    *Third Department of Pediatrics, National and Kapodistrian University of Athens, General University Hospital "Attikon" †Department of Immunology & Histocompatibility, Specific Reference Centre for Primary Immunodeficiencies-Paediatric Immunology, "Aghia Sophia" Children's Hospital, Athens, Greece.
    Wiskott-Aldrich syndrome (WAS) is a rare X-linked immunodeficiency characterized by various clinical phenotypes. We report the case of a 3-year-old immigrant boy presenting with persistent infant-onset thrombocytopenia treated for refractory immune thrombocytopenic purpura. Sequence analysis confirmed the diagnosis of WAS. Read More

    Successful Reduced Intensity Conditioning Alternate Donor Stem Cell Transplant for Wiskott-Aldrich Syndrome.
    J Pediatr Hematol Oncol 2017 Nov;39(8):e493-e496
    Pediatric Hematology Oncology and Bone Marrow Transplant Unit, Department of Pediatrics, Fortis Memorial Research Institute, Gurgaon, Haryana, India.
    There are very few reports of reduced intensity conditioning (RIC) hematopoietic stem cell transplant (HSCT) with alternate donor for Wiskott-Aldrich syndrome (WAS) and there is no report of RIC with posttransplant cyclophosphamide (PTCy) in WAS. There is only 1 report of T cell receptor αβ and CD19-depleted haploidentical HSCT for WAS. Here we report successful outcome in 3 children with WAS who underwent successful RIC alternate donor HSCT of whom 2 (matched unrelated donor and T-cell replete haploidentical) received PTCy and 1 underwent T cell receptor αβ and CD19-depleted haploidentical HSCT. Read More

    Platelets in Wiskott-Aldrich syndrome: victims or executioners?
    J Leukoc Biol 2017 Aug 29. Epub 2017 Aug 29.
    Division of Regenerative Medicine, Stem Cells and Gene Therapy, San Raffaele Telethon Institute for Gene Therapy, San Raffaele Scientific Institute, Milan, Italy;
    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. Read More

    A map of human circular RNAs in clinically relevant tissues.
    J Mol Med (Berl) 2017 Nov 25;95(11):1179-1189. Epub 2017 Aug 25.
    Max Delbrück Center for Molecular Medicine (MDC), Robert-Rössle-Strasse 10, 13125, Berlin, Germany.
    Cellular circular RNAs (circRNAs) are generated by head-to-tail splicing and are present in all multicellular organisms studied so far. Recently, circRNAs have emerged as a large class of RNA which can function as post-transcriptional regulators. It has also been shown that many circRNAs are tissue- and stage-specifically expressed. Read More

    Crystal Structure of Leiomodin 2 in Complex with Actin: A Structural and Functional Reexamination.
    Biophys J 2017 Aug;113(4):889-899
    Department of Physiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. Electronic address:
    Leiomodins (Lmods) are a family of actin filament nucleators related to tropomodulins (Tmods), which are pointed end-capping proteins. Whereas Tmods have alternating tropomyosin- and actin-binding sites (TMBS1, ABS1, TMBS2, ABS2), Lmods lack TMBS2 and half of ABS1, and present a C-terminal extension containing a proline-rich domain and an actin-binding Wiskott-Aldrich syndrome protein homology 2 (WH2) domain that is absent in Tmods. Most of the nucleation activity of Lmods resides within a fragment encompassing ABS2 and the C-terminal extension. Read More

    The Role of Rho-GTPases and actin polymerization during Macrophage Tunneling Nanotube Biogenesis.
    Sci Rep 2017 Aug 17;7(1):8547. Epub 2017 Aug 17.
    Department of Anatomy and Structural Biology, Albert Einstein College of Medicine, 1300 Morris Park Ave, Gruss MRRC 306, Bronx, NY, 10461, USA.
    Macrophage interactions with other cells, either locally or at distances, are imperative in both normal and pathological conditions. While soluble means of communication can transmit signals between different cells, it does not account for all long distance macrophage interactions. Recently described tunneling nanotubes (TNTs) are membranous channels that connect cells together and allow for transfer of signals, vesicles, and organelles. Read More

    Biological and functional characterization of bone marrow-derived mesenchymal stromal cells from patients affected by primary immunodeficiency.
    Sci Rep 2017 Aug 15;7(1):8153. Epub 2017 Aug 15.
    Department of Pediatric Hematology/Oncology, IRCCS Bambino Gesù Children's Hospital, Rome, Italy.
    Mesenchymal stromal cells (MSCs) represent a key component of bone marrow (BM) microenvironment and display immune-regulatory properties. We performed a detailed analysis of biological/functional properties of BM-MSCs derived from 33 pediatric patients affected by primary immune-deficiencies (PID-MSCs): 7 Chronic Granulomatous Disease (CGD), 15 Wiskott-Aldrich Syndrome (WAS), 11 Severe Combined Immunodeficiency (SCID). Results were compared with MSCs from 15 age-matched pediatric healthy-donors (HD-MSCs). Read More

    The dock-and-coalesce mechanism for the association of a WASP disordered region with the Cdc42 GTPase.
    FEBS J 2017 Oct 30;284(20):3381-3391. Epub 2017 Aug 30.
    Department of Physics and Institute of Molecular Biophysics, Florida State University, Tallahassee, FL, USA.
    Intrinsically disordered proteins (IDPs) play key roles in signaling and regulation. Many IDPs undergo folding upon binding to their targets. We have proposed that coupled folding and binding of IDPs generally follow a dock-and-coalesce mechanism, whereby a segment of the IDP, through diffusion, docks to its cognate subsite and, subsequently, the remaining segments coalesce around their subsites. Read More

    Wiskott-Aldrich syndrome protein: Emerging mechanisms in immunity.
    Eur J Immunol 2017 11 12;47(11):1857-1866. Epub 2017 Sep 12.
    UCL Great Ormond Street Institute of Child Health, London.
    The Wiskott-Aldrich syndrome protein (WASP) participates in innate and adaptive immunity through regulation of actin cytoskeleton-dependent cellular processes, including immune synapse formation, cell signaling, migration and cytokine release. There is also emerging evidence for a direct role in nuclear transcription programmes uncoupled from actin polymerization. A deeper understanding of some of the more complex features of Wiskott Aldrich syndrome (WAS) itself, such as the associated autoimmunity and inflammation, has come from identification of defects in the number and function of anti-inflammatory myeloid cells and regulatory T and B cells, as well as defects in positive and negative B-cell selection. Read More

    p63α protein up-regulates heat shock protein 70 expression via E2F1 transcription factor 1, promoting Wasf3/Wave3/MMP9 signaling and bladder cancer invasion.
    J Biol Chem 2017 09 9;292(38):15952-15963. Epub 2017 Aug 9.
    From the Nelson Institute of Environmental Medicine, New York University School of Medicine, Tuxedo, New York 10987,
    Bladder cancer (BC) is the sixth most common cancer in the United States and is the number one cause of death among patients with urinary system malignancies. This makes the identification of invasive regulator(s)/effector(s) as the potential therapeutic targets for managing BC a high priority. p63 is a member of the p53 family of tumor suppressor genes/proteins, plays a role in the differentiation of epithelial tissues, and is believed to function as a tumor suppressor. Read More

    Conditional knock out of N-WASP in keratinocytes causes skin barrier defects and atopic dermatitis-like inflammation.
    Sci Rep 2017 Aug 4;7(1):7311. Epub 2017 Aug 4.
    School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637551, Republic of Singapore.
    Neural-Wiskott Aldrich Syndrome Protein (N-WASP) is expressed ubiquitously and regulates actin cytoskeleton remodeling. In order to characterize the role of N-WASP in epidermal homeostasis and cutaneous biology, we generated conditional N-WASP knockout mouse using CK14-cre (cytokeratin 14) to ablate expression of N-WASP in keratinocytes. N-WASPK14KO (N-WASP fl/fl ; CK14-Cre) mice were born following Mendelian genetics suggesting that N-WASP expression in keratinocytes is not essential during embryogenesis. Read More

    Selected signalling proteins recruited to the T-cell receptor-CD3 complex.
    Immunology 2018 Jan 5;153(1):42-50. Epub 2017 Sep 5.
    Centre of Excellence in Medical Biotechnology, Faculty of Medical Science, Naresuan University, Phitsanulok, Thailand.
    The T-cell receptor (TCR)-CD3 complex, expressed on T cells, determines the outcome of a T-cell response. It consists of the TCR-αβ heterodimer and the non-covalently associated signalling dimers of CD3εγ, CD3εδ and CD3ζζ. TCR-αβ binds specifically to a cognate peptide antigen bound to an MHC molecule, whereas the CD3 subunits transmit the signal into the cytosol to activate signalling events. Read More

    Gene therapy for Wiskott-Aldrich syndrome in a severely affected adult.
    Blood 2017 09 17;130(11):1327-1335. Epub 2017 Jul 17.
    Institute of Child Health, University College London, London, United Kingdom.
    Until recently, hematopoietic stem cell transplantation was the only curative option for Wiskott-Aldrich syndrome (WAS). The first attempts at gene therapy for WAS using a ϒ-retroviral vector improved immunological parameters substantially but were complicated by acute leukemia as a result of insertional mutagenesis in a high proportion of patients. More recently, treatment of children with a state-of-the-art self-inactivating lentiviral vector (LV-w1. Read More

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