Sash3-KO Mouse

SASH3, also called SH3-containing lymphocyte protein (SLY1), is a putative adaptor protein. It contains sterile alpha motif (SAM) and Src homology-3 (SH3) domains and is postulated to play a crucial role in organizing signaling complexes and signal transduction cascades in lymphocytes [1,5]. It may be involved in pathways like natural killer cell-mediated cytotoxicity, Th17 cell differentiation, PD-L1 expression and PD-1 checkpoint pathway in cancer, NF-kappa B signaling pathway, B-cell receptor signaling pathway, and Toll-like receptor signaling pathway [3].

In humans, 3 novel SASH3 deleterious variants were identified in 4 male patients with combined immunodeficiency and immune dysregulation. These patients had recurrent infections and autoimmune cytopenias, along with lymphopenia in CD4+ T-cells, B-cells, and natural killer cells, as well as decreased T-cell proliferation and increased apoptosis [1]. A case of an adult patient initially diagnosed with common variable immunodeficiency was later found to have a SASH3 gene loss-of-function variant, presenting with abnormal T-cell activation and proliferation [2]. Also, a patient with Evans syndrome was found to have a germline mutation in SASH3, associated with impaired T-cell proliferation and immunophenotypic changes [4].

In conclusion, SASH3 is essential for lymphocyte function and survival. Studies on SASH3-deficient patients, similar to the phenotypes seen in Sly1-/-and Sly1Δ/Δ mice, highlight its role in human immune-related diseases, including combined immunodeficiency, immune dysregulation, and autoimmune cytopenias [1].

References:

1. Delmonte, Ottavia M, Bergerson, Jenna R E, Kawai, Tomoki, Murphy, Philip M, Notarangelo, Luigi D. . SASH3 variants cause a novel form of X-linked combined immunodeficiency with immune dysregulation. In Blood, 138, 1019-1033. doi:10.1182/blood.2020008629. https://pubmed.ncbi.nlm.nih.gov/33876203/

2. Labrador-Horrillo, Moisés, Franco-Jarava, Clara, Garcia-Prat, Marina, Martinez-Gallo, Mónica, Colobran, Roger. 2022. Case Report: X-Linked SASH3 Deficiency Presenting as a Common Variable Immunodeficiency. In Frontiers in immunology, 13, 881206. doi:10.3389/fimmu.2022.881206. https://pubmed.ncbi.nlm.nih.gov/35464398/

3. Chen, Xi, Yuan, Yixiao, Ren, Wenjun, Niu, Xiaoqun, Jiang, Xiulin. 2022. Pan-Cancer Integrated Analysis Identification of SASH3, a Potential Biomarker That Inhibits Lung Adenocarcinoma Progression. In Frontiers in oncology, 12, 927988. doi:10.3389/fonc.2022.927988. https://pubmed.ncbi.nlm.nih.gov/35756681/

4. Novak, Wolfgang, Berner, Jakob, Svaton, Michael, Kager, Leo, Boztug, Kaan. 2023. Evans syndrome caused by a deleterious mutation affecting the adaptor protein SASH3. In British journal of haematology, 203, 678-683. doi:10.1111/bjh.19061. https://pubmed.ncbi.nlm.nih.gov/37646304/

5. Jaufmann, Jennifer, Franke, Fabian Christoph, Sperlich, Andreas, Janssen, Klaus-Peter, Beer-Hammer, Sandra. . The emerging and diverse roles of the SLy/SASH1-protein family in health and disease-Overview of three multifunctional proteins. In FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 35, e21470. doi:10.1096/fj.202002495R. https://pubmed.ncbi.nlm.nih.gov/33710696/