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SASH3 variants cause a novel form of X-linked combined immunodeficiency with immune dysregulation

  1. Author:
    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,Dani
    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,Doug
    Urrutia, Raul
    Rosenzweig, Sergio D.
    Walkiewicz, Magdalena A.
    Murphy, Philip M.
    Notarangelo, Luigi D.

  2. Author Address

    NIAID, Lab Clin Immunol & Microbiol, Div Intramural Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.NIH, Dept Lab Med, Clin Ctr, Bldg 10, Bethesda, MD 20892 USA.NIAID, Mol Signaling Sect, Lab Mol Immunol, Div Intramural Res,NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.NINDS, Neuroimmunol Clin, Div Neuroimmunol & Neurovirol, NIH, Bldg 36,Rm 4D04, Bethesda, MD 20892 USA.Genom Sci & Precis Med Ctr, Div Res, Milwaukee, WI USA.Med Coll Wisconsin, Clin & Translat Sci Inst, Milwaukee, WI 53226 USA.Leidos Biomed Res Inc, Frederick Natl Lab Canc Res, Appl Dev Res Directorate, Frederick, MD USA.Univ Florence, Dept Expt & Clin Med, Florence, Italy.NCI, Pediat Oncol Branch, NIH, Bethesda, MD 20892 USA.Univ Montpellier, CNRS, Inst Genet Mol Montpellier, Unite Mixte Rech UMR 5535, Montpellier, France.NIH, Hematol Sect, Dept Lab Med, Clin Ctr, Bldg 10, Bethesda, MD 20892 USA.Queensland Univ Technol, Fac Hlth, Ctr Immunol & Infect Control, Sch Biomed Sci, Brisbane, Qld, Australia.NIAID, Lab Infect Dis, Div Intramural Res, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.NIAID, Div Intramural Res, Lab Allerg Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA.Med Coll Wisconsin, Dept Surg, 8700 W Wisconsin Ave, Milwaukee, WI 53226 USA.
    1. Year: 2021
    2. Date: Sep 23
  2. Journal: BLOOD
  3. AMER SOC HEMATOLOGY,
    1. 138
    2. 12
    3. Pages: 1019-1033
  5. Type of Article: Article
  6. ISSN: 0006-4971
  1. Abstract:

    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 a (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 Sly1 Delta/Delta mutations, highlighting an important role of SASH3 in human lymphocyte function and survival.

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External Sources

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  2. DOI: 10.1182/blood.2020008629
  3. PMID: 33876203
  4. PMCID: PMC8462359
  5. View record in Web of Science®
  6. WOS: 000704378100005

Library Notes

  1. Fiscal Year: FY2021-2022
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