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SASH3 variants cause a novel form of X-linked combined immunodeficiency with immune dysregulation.
Delmonte, Ottavia M; Bergerson, Jenna R E; Kawai, Tomoki; Kuehn, Hye Sun; McDermott, David H; Cortese, Irene; Zimmermann, Michael T; Dobbs, A Kerry; Bosticardo, Marita; Fink, Danielle; Majumdar, Shamik; Palterer, Boaz; Pala, Francesca; Dsouza, Nikita R; Pouzolles, Marie; Taylor, Naomi; Calvo, Katherine R; Daley, Stephen R; Velez, Daniel; Agharahimi, Anahita; Myint-Hpu, Katherine; Dropulic, Lesia K; Lyons, Jonathan J; Holland, Steven M; Freeman, Alexandra F; Ghosh, Rajarshi; Similuk, Morgan B; Niemela, Julie E; Stoddard, Jennifer; Kuhns, Douglas B; Urrutia, Raul; Rosenzweig, Sergio D; Walkiewicz, Magdalena A; Murphy, Philip M; Notarangelo, Luigi D.
Afiliación
  • Delmonte OM; Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
  • Bergerson JRE; Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
  • Kawai T; Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
  • Kuehn HS; Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD.
  • McDermott DH; Molecular Signaling Section, Laboratory of Molecular Immunology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
  • Cortese I; Neuroimmunology Clinic, Division of Neuroimmunology and Neurovirology, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD.
  • Zimmermann MT; Division of Research, Genomics Sciences & Precision Medicine Center, Milwaukee, WI.
  • Dobbs AK; Clinical and Translational Sciences Institute, Medical College of Wisconsin, Milwaukee, WI.
  • Bosticardo M; Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
  • Fink D; Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
  • Majumdar S; Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD.
  • Palterer B; Molecular Signaling Section, Laboratory of Molecular Immunology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
  • Pala F; Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
  • Dsouza NR; Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
  • Pouzolles M; Division of Research, Genomics Sciences & Precision Medicine Center, Milwaukee, WI.
  • Taylor N; Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD.
  • Calvo KR; Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD.
  • Daley SR; Institut de Genetique Moleculaire de Montpellier, Centre National de la Recherche Scientifique Unité Mixte de Recherche (UMR) 5535, Universite de Montpellier, Montpellier, France.
  • Velez D; Hematology Section, Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD.
  • Agharahimi A; Centre for Immunology and Infection Control, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD, Australia.
  • Myint-Hpu K; Molecular Signaling Section, Laboratory of Molecular Immunology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
  • Dropulic LK; Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
  • Lyons JJ; Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
  • Holland SM; Laboratory of Infectious Disease and.
  • Freeman AF; Division of Intramural Research, Laboratory of Allergic Diseases, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD and.
  • Ghosh R; Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
  • Similuk MB; Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
  • Niemela JE; Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
  • Stoddard J; Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.
  • Kuhns DB; Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD.
  • Urrutia R; Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD.
  • Rosenzweig SD; Applied/Developmental Research Directorate, Leidos Biomedical Research, Inc, Frederick National Laboratory for Cancer Research, Frederick, MD.
  • Walkiewicz MA; Division of Research, Genomics Sciences & Precision Medicine Center, Milwaukee, WI.
  • Murphy PM; Department of Surgery, Medical College of Wisconsin, Milwaukee, WI.
  • Notarangelo LD; Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD.
Blood ; 138(12): 1019-1033, 2021 09 23.
Article en En | MEDLINE | ID: mdl-33876203
Sterile alpha motif (SAM) and Src homology-3 (SH3) domain-containing 3 (SASH3), also called SH3-containing lymphocyte protein (SLY1), is a putative adaptor protein that is postulated to play an important role in the organization of signaling complexes and propagation of signal transduction cascades in lymphocytes. The SASH3 gene is located on the X-chromosome. Here, we identified 3 novel SASH3 deleterious variants in 4 unrelated male patients with a history of combined immunodeficiency and immune dysregulation that manifested as recurrent sinopulmonary, cutaneous, and mucosal infections and refractory autoimmune cytopenias. Patients exhibited CD4+ T-cell lymphopenia, decreased T-cell proliferation, cell cycle progression, and increased T-cell apoptosis in response to mitogens. In vitro T-cell differentiation of CD34+ cells and molecular signatures of rearrangements at the T-cell receptor α (TRA) locus were indicative of impaired thymocyte survival. These patients also manifested neutropenia and B-cell and natural killer (NK)-cell lymphopenia. Lentivirus-mediated transfer of the SASH3 complementary DNA-corrected protein expression, in vitro proliferation, and signaling in SASH3-deficient Jurkat and patient-derived T cells. These findings define a new type of X-linked combined immunodeficiency in humans that recapitulates many of the abnormalities reported in mice with Sly1-/- and Sly1Δ/Δ mutations, highlighting an important role of SASH3 in human lymphocyte function and survival.
Asunto(s)

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Cromosomas Humanos X / Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X / Mutación Tipo de estudio: Prognostic_studies Límite: Animals / Child, preschool / Humans / Male Idioma: En Revista: Blood Año: 2021 Tipo del documento: Article

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Cromosomas Humanos X / Enfermedades por Inmunodeficiencia Combinada Ligada al Cromosoma X / Mutación Tipo de estudio: Prognostic_studies Límite: Animals / Child, preschool / Humans / Male Idioma: En Revista: Blood Año: 2021 Tipo del documento: Article