SAM- and SH3 domain-containing protein 3; SASH3, also known as SH3 containing Lymphocyte Protein (SLY1) encodes an adaptor scaffolding protein that is vital for integration and propagation of signal transduction cascades in lymphocytes. SASH3 protein is phosphorylated at Ser27 following T- or B-cell receptor ligation and protein kinase C (PKC) activation. The phenotype associated with combined immunodeficiency due to SASH3 variants is characterized by recurrent infections and multilineage immunodeficiency.
SASH3 was first reported in relation to combined immunodeficiency X- linked in 2021 (Delmonte et al., PMID: 33876203). The study reported four unrelated male patients carrying three hemizygous LOF variants in the SASH3 gene. Patients manifested in early childhood with recurrent sinopulmonary, cutaneous, and mucosal infections, and refractory autoimmune cytopenias. Horrillo et al., 2022 reported a man with a milder form of combined immunodeficiency and a novel truncating SASH3 variant which led to a complete absence of the protein (PMID: 35464398). The reported patients exhibited CD4+ T-cell lymphopenia, defective T cell activation and proliferation, and B cell lymphopenia. Mother heterozygosity was confirmed in three of the five patients reported.
This gene-disease relationship is also supported by rescue, animal model and expression evidence. Correction of the proliferative defect of SASH3−/− Jurkat cells occurred upon transduction with the SASH3 LV vector. Transduction efficiency was also evident by reconstitution of PLCγ1 phosphorylation in SASH3-transduced Patient T cells upon in vitro stimulation with anti-CD3 and anti-CD28 (PMID: 33876203). Two different Sly1 deficient mice models recapitulated the human phenotype (PMIDs: 16227612 and 19604361). Both Sly1Δ/Δ and Sly1-/- showed that absence of SLY1 protein affects CD4 T cell development, T-cell proliferation, and cytokine production and impairs antibody response to T- dependent and T- independent antigens. Preferential SASH3 expression in lymph nodes and thymus gland indicates an essential role in the development and activation of lymphocytes (PMIDs: 24309898 and 25970244).
In summary, SASH3 is definitively associated with combined immunodeficiency X-linked. This has been repeatedly demonstrated in both research and diagnostic settings and has been upheld over time.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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