Alternative titles; symbols
HGNC Approved Gene Symbol: SASH3
Cytogenetic location: Xq26.1 Genomic coordinates (GRCh38): X:129,779,949-129,795,201 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xq26.1 | Immunodeficiency 102 | 301082 | X-linked recessive | 3 |
SLY contains an Src homology-3 (SH3) domain and a sterile alpha motif (SAM), both of which are found in proteins involved in cell signaling (Beer et al., 2001).
The SASH3 gene encodes an adaptor scaffolding protein that is mainly expressed in lymphocytes and is important for T-cell proliferation, activation, and cell survival (summary by Delmonte et al., 2021).
By expression cloning for adhesion to endothelial cells, Beer et al. (2001) cloned Sly from a mouse T-cell lymphoma cDNA library. They identified human SLY by searching databases for homology with mouse Sly. The deduced mouse and human proteins contain 381 amino acids and share 94% sequence identity. SLY has a central SH3 domain and a SAM motif in its C-terminal half. It does not have a signal peptide or transmembrane region. Northern blot analysis detected expression in lung, spleen, Peyer patches, lymph node, thymus, and bone marrow. Expression was also detected in all murine T- and B-lymphoma cell lines examined. In situ hybridization of mouse sections revealed expression limited to the T- and B-cell areas of lymph nodes, the medulla and cortex of thymus, and Peyer patches of gut; expression was not detected in lung.
By genomic sequence analysis, Beer et al. (2001) mapped the SLY gene to chromosome Xq25-q26.3.
Stumpf (2022) mapped the SASH3 gene to chromosome Xq26.1 based on an alignment of the SASH3 sequence (GenBank AK292023) with the genomic sequence (GRCh38).
In 4 unrelated men with immunodeficiency-102 (IMD102; 301082), Delmonte et al. (2021) identified hemizygous mutations in the SASH3 gene (300441.0001-300441.0003). One patient carried a missense mutation and the other 3 had a nonsense mutation. The mutations, which were found by whole-exome sequencing, were demonstrated to be inherited from the unaffected mother in 2 cases. None of the mutations were present in the gnomAD database. Patient-derived T cells showed decreased proliferation, decreased cell cycle progression, disturbed differentiation, and increased apoptosis compared to controls. Patient-derived T cells also showed a defect in TCR activation and signaling, as well as defects in TCR rearrangements and diversity, consistent with functional defects. In vitro cellular expression studies showed that these defects could be restored by expression of wildtype SASH3. The functional T-cell defects likely played a role in the increased susceptibility to infection observed in the patients. In addition, the authors suggested that SASH3 deficiency may perturb mechanisms of negative selection in the thymus, thus facilitating the development of autoimmunity in addition to immunodeficiency. Overall, the findings were consistent with a loss of SASH3 function. The patients had recurrent infections and immune dysregulation manifest as refractory autoimmune cytopenias affecting all lineages.
In a 43-year-old man with IMD102, Labrador-Horrillo et al. (2022) identified a hemizygous nonsense mutation in the SASH3 gene (Q169X; 300441.0004). The mutation, which was found by targeted next-generation sequencing and confirmed by Sanger sequencing, was inherited from the unaffected mother. It was not present in the major population databases. Western blot analysis of patient cells showed complete absence of the SASH3 protein, confirming that the mutation results in a loss of function. Additional functional studies were not performed. The patient had immunodeficiency, but did not have autoimmune cytopenias or obvious immune dysregulation.
Beer et al. (2005) generated mice homozygous for a Sly1 mutation that resulted in a functionally inactive protein lacking the phosphorylation site at ser27 and a functional nuclear localization signal. Mutant mice were born at normal mendelian ratios, were fertile, and did not exhibit any gross anatomic or behavioral abnormalities. However, mutant mice had reduced lymphoid organ sizes, diminished marginal zone B-cell numbers, and severely impaired antibody responses against T-dependent and -independent antigens. In vitro analysis with cells from mutant mice showed that impaired immune responses were due to attenuated B- and T-cell proliferation and severely reduced T-cell cytokine production. Analysis with a mouse model of heterotopic heart transplantation revealed that the Sly1 mutation also affected T-cell responses in vivo, and consequently survival of semi-identical cardiac allografts was substantially prolonged in mutant mice. The mutant Sly1 protein localized exclusively to cytoplasm, indicating that, in addition to phosphorylation of ser27, nuclear localization of Sly1 is also essential for its function.
Reis et al. (2009) found that Sly1 -/- mice were born at normal mendelian ratios, appeared healthy, and were fertile. However, Sly1 -/- mice displayed a reduction in thymocyte cellularity of lymphoid organs. In line with reduced thymocyte cellularity, Sly1 -/- mice exhibited delayed T-cell development, as loss of Sly1 partially blocked developmental progression of double-negative (DN) thymocytes, leading to defects in proliferation and differentiation of DN thymocytes to double-positive (DP) thymocytes. Activation of Mtor (601231) signaling was partially impaired in DN thymocytes. Moreover, Sly1 was identified as an antiapoptotic protein required for developmental progression of DN thymocytes, as increased apoptosis induction was seen in Sly1 -/- DN3 thymocytes. Further analysis showed that Sly1 phosphorylation was differentially regulated in early thymocytes for the prevention of premature apoptosis initiation in developing thymocytes.
In a 19-year-old man (P1) with immunodeficiency-102 (IMD102; 301082), Delmonte et al. (2021) identified a hemizygous c.1039C-T transition in the SASH3 gene, resulting in an arg347-to-cys (R347C) substitution at the C terminus. The mutation, which was found by whole-exome sequencing, was inherited from the unaffected mother. It was not present in the gnomAD database. Western blot analysis of patient cells showed a normal-sized product at slightly reduced levels compared to controls. Molecular modeling suggested that the mutation may alter a regulatory phosphorylation mark and disrupt SASH3 activity. Patient T cells showed decreased proliferation and cell cycle progression and increased apoptosis compared to controls. There were also functional signaling defects of the TCR.
In 2 unrelated men, P2, who was 50, and P3, who died at age 27, with immunodeficiency-102 (IMD102; 301082), Delmonte et al. (2021) identified a hemizygous c.862C-T transition in the SASH3 gene, resulting in an arg288-to-ter (R288X) substitution in the SAM domain. The mutation, which was found by whole-exome sequencing, was inherited from the unaffected mother of P3; the mother of P2 was not available. The mutation was not present in the gnomAD database. Western blot analysis of patient cells showed absence of SASH3 expression, likely due to nonsense-mediated mRNA decay. The authors postulated a loss of function. Patient T cells showed decreased proliferation and cell cycle progression and increased apoptosis compared to controls. There were also functional signaling defects of the TCR.
In a 56-year-old man (P4) with immunodeficiency-102 (IMD102; 301082), Delmonte et al. (2021) identified a hemizygous c.733C-T transition in the SASH3 gene, resulting in an arg245-to-ter (R245X) substitution between the SH3 and SAM domains. The mutation was found by whole-exome sequencing and was not present in the gnomAD database. Western blot analysis of patient cells showed absence of SASH3 expression, likely due to nonsense-mediated mRNA decay. The authors postulated a loss of function. Patient T cells showed decreased proliferation and cell cycle progression and increased apoptosis compared to controls. There were also functional signaling defects of the TCR. These abnormalities could be rescued in vitro with wildtype SASH3 in cells expressing the mutation. The patient died of JC virus-positive progressive multifocal leukoencephalopathy (PML).
In a 43-year-old man with immunodeficiency-102 (IMD102; 301082), Labrador-Horrillo et al. (2022) identified a hemizygous c.505C-T transition in the SASH3 gene, resulting in a gln169-to-ter (Q169X) substitution. The mutation, which was found by targeted next-generation sequencing and confirmed by Sanger sequencing, was inherited from the unaffected mother. It was not present in the major population databases. Western blot analysis of patient cells showed complete absence of the SASH3 protein, confirming that the mutation results in a loss of function. Additional functional studies were not performed. The patient had immunodeficiency, but did not have autoimmune cytopenias or obvious immune dysregulation.
Beer, S., Scheikl, T., Reis, B., Huser, N., Pfeffer, K., Holzmann, B. Impaired immune responses and prolonged allograft survival in Sly1 mutant mice. Molec. Cell. Biol. 25: 9646-9660, 2005. [PubMed: 16227612] [Full Text: https://doi.org/10.1128/MCB.25.21.9646-9660.2005]
Beer, S., Simins, A. B., Schuster, A., Holzmann, B. Molecular cloning and characterization of a novel SH3 protein (SLY) preferentially expressed in lymphoid cells. Biochim. Biophys. Acta 1520: 89-93, 2001. [PubMed: 11470164] [Full Text: https://doi.org/10.1016/s0167-4781(01)00242-1]
Delmonte, O. M., Bergerson, J. R. E., Kawai, T., Kuehn, H. S., McDermott, D. H., Cortese, I., Zimmermann, M. T., Dobbs, A. K., Bosticardo, M., Fink, D., Majumdar, S., Palterer, B., and 23 others. SASH3 variants cause a novel form of X-linked combined immunodeficiency with immune dysregulation. Blood 138: 1019-1033, 2021. [PubMed: 33876203] [Full Text: https://doi.org/10.1182/blood.2020008629]
Labrador-Horrillo, M., Franco-Jarava, C., Garcia-Prat, M., Parra-Martinez, A., Antolin, M., Salgado-Perandres, S., Aguilo-Cucurull, A., Martinez-Gallo, M., Colobran, R. Case report: X-linked SASH3 deficiency presenting as a common variable immunodeficiency. Front. Immun. 13: 881206, 2022. [PubMed: 35464398] [Full Text: https://doi.org/10.3389/fimmu.2022.881206]
Reis, B., Pfeffer, K., Beer-Hammer, S. The orphan adapter protein SLYI as a novel anti-apoptotic protein required for thymocyte development. BMC Immun. 10: 38, 2009. [PubMed: 19604361] [Full Text: https://doi.org/10.1186/1471-2172-10-38]
Stumpf, A. M. Personal Communication. Baltimore, Md. 05/31/2022.