SASH3variants cause a novel form of X-linked combined immunodeficiency with immune dysregulation

Abstract

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.

Antibody responses to the SARS-CoV-2 vaccine in individuals with various inborn errors of immunity

“…19,20 One patient with SASH3 deficiency failed to make anti-S IgG after 2 doses of an mRNA vaccine, which is consistent with the disease phenotype. 21 In the immunodeficient cohort, a CD3 1 cell count of less than 1000 cells/mL at baseline (before vaccination) was associated with lower anti-S IgG levels at the second time point after immunization (Fig 2, A). Furthermore, patients with CD19 1 cell counts of less than 100 cells/mL at baseline had a significantly lower GM of anti-S IgG levels than did patients with a CD19 1 cell count of 100 cells/mL or higher both after the first dose (60,621 LU Most patients receiving immunoglobulin replacement therapy developed protective anti-S antibody titers, and the only 2 patients (patients 10 and 75 [see Table E1]) who tested positive for anti-N antibodies after immunization had a history of SARS-CoV-2 infection, which is consistent with the fact that most currently available immunoglobulin preparations are not derived from SARS-CoV-2-exposed donors (Fig 3, A).…”

Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee

“…Novel gene defects have been found for most categories of IEI, including novel causes of: Combined immunodeficiencies ( LCP2 (SLP76) [ 12 ], PAX1 [ 13 , 14 ], ITPKB [ 15 ]; SASH3 [ 16 , 17 ], MAN2B2 [ 18 ], COPG1 [ 19 ], IKZF2 [ 20 – 23 ], CHUK [ 24 ], IKZF3 [ 25 , 26 ], CRACR2A [ 27 ], CD28 [ 28 ]) (Table 1 ; Supplementary Table 1 ); Combined immunodeficiencies with syndromic features ( MCM10 [ 29 , 30 ], IL6ST [ 31 – 33 ], DIAPH1 [ 34 ]) (Table 2 ; Supplementary Table 1 ); B cell deficiencies, agammaglobulinemia, or hypogammaglobulinemia ( FNIP1 [ 35 , 36 ], SP1I [ 37 ] , PIK3CG [ 38 , 39 ], POU2AF1 [ 40 ], CTNNBL1 [ 41 ], TNSRSF13 [ 42 ]) (Table 3 ; Supplementary Table 1 ); Immune dysregulation ( RHOG [ 43 ], SOCS1 [ 44 – 46 ], PDCD1 [ 47 ], ELF4 [ 48 , 49 ], TET2 [ 50 ], CEBPE [ 51 ], IKZF1 GOF [ 52 ]) (Table 4 ; Supplementary Table 1 ) neutropenia CXCR2 [ 53 ...…”

“…There can be clinical overlap between some genes listed here and those listed in Table 7 Total number of mutant genes: 66. New inborn errors of immunity: 8 ( SLP76 [ 12 ], PAX1 [ 13 , 14 ], ITPKB [ 15 ]; SASH3 [ 16 , 17 ], MAN2B2 [ 18 ], COPG1 [ 19 ], IKZF2 [ 20 – 23 ], CHUK [ 24 ]) SCID severe combined immunodeficiency, CID combined immunodeficiency, EBV Epstein-Barr virus, MHC major histocompatibility complex, HPV human papillomavirus, Treg T regulatory cell, XL X-linked inheritance, AR autosomal recessive inheritance, AD autosomal dominant inheritance, LOF loss-of-function, GOF gain-of-function, FTT failure to thrive…”

“…Combined immunodeficiencies ( LCP2 (SLP76) [ 12 ], PAX1 [ 13 , 14 ], ITPKB [ 15 ]; SASH3 [ 16 , 17 ], MAN2B2 [ 18 ], COPG1 [ 19 ], IKZF2 [ 20 – 23 ], CHUK [ 24 ], IKZF3 [ 25 , 26 ], CRACR2A [ 27 ], CD28 [ 28 ]) (Table 1 ; Supplementary Table 1 );…”

Comprehensive Analysis of Prognostic Microenvironment-Related Genes in Invasive Breast Cancer

“…It has been reported that SASH3 functions as an adaptor protein in lymphocytes (40)(41)(42). Recent study showed that SASH3 is important for T-cell proliferation, activation and cell survival, and lack or mutation of SASH3 could lead to a new type disease of human X-linked combined immunodeficiency, which was manifested as CD4 + T-cell lymphopenia, decreased Tcell proliferation, cell cycle progression, and increased T-cell apoptosis in response to mitogens (43). However, the precise function of SASH3 remains unknown.…”