SAM and 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 three novel SASH3 deleterious variants in four unrelated male patients with a history of combined immunodeficiency and immune dysregulation manifesting as recurrent sinopulmonary, cutaneous and mucosal infections, and refractory autoimmune cytopenias. Patients exhibited CD4+ T cell lymphopenia, decreased T cell proliferation and 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 alpha (TRA) locus were indicative of impaired thymocyte survival. These patients also manifested neutropenia and B and NK cell lymphopenia. Lentivirus-mediated transfer of the SASH3 cDNA 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 Sly1-/- and Sly1D/Dmutant mice, highlighting an important role of SASH3 in human lymphocyte function and survival.
Ottavia M Delmonte, Jenna Ruth Ember Bergerson, Tomoki Kawai, Hye Sun Kuehn, David H McDermott, Irene Cortese, Michael T Zimmermann, Kerry Dobbs, Marita Bosticardo, Danielle Fink, Shamik Majumdar, Boaz Palterer, Francesca Pala, Nikita R Dsouza, Marie Pouzolles, Naomi Taylor, Katherine Rainsford Calvo, Stephen R Daley, Daniel S Velez, Anahita Agharahimi, Katherine Myint-Hpu, Lesia Dropulic, Jonathan J Lyons, Steven M Holland, Alexandra F Freeman, Rajarshi Ghosh, Morgan N Similuk, Julie E Niemela, Jennifer L Stoddard, Douglas B Kuhns, Raul Urrutia, Sergio Rosenzweig, Magdalena A Walkiewicz, Philip Murphy, Luigi D Notarangelo