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Other entities represented in this entry:
HGNC Approved Gene Symbol: SSX1
Cytogenetic location: Xp11.23 Genomic coordinates (GRCh38): X:48,255,392-48,267,444 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xp11.23 | Spermatogenic failure, X-linked, 5 | 301099 | X-linked | 3 |
SSX1 is a primate-specific gene expressed primarily in testis (summary by Liu et al., 2023).
Human synovial sarcomas (300813) contain a recurrent and specific chromosomal translocation t(X;18)(p11.2;q11.2). By screening a synovial sarcoma cDNA library with a YAC spanning the X chromosome breakpoint, Clark et al. (1994) identified a hybrid transcript that contained 5-prime sequences (designated SYT by them; see SS18; 600192) mapping to chromosome 18 and 3-prime sequences (designated SSX by them) mapping to the X chromosome. An SYT probe detected genomic rearrangements in 10 of 13 synovial sarcomas. Sequencing of cDNA clones showed that the normal SYT gene encodes a protein rich in glutamine, proline, and glycine and that in synovial sarcoma, rearrangement of the SYT gene results in the formation of an SYT-SSX fusion protein.
Crew et al. (1995) demonstrated that the t(X;18)(p11.2;q11.2) found in human synovial sarcoma results in the fusion of the chromosome 18 SS18 gene (SYT) to either of 2 distinct genes, SSX1 or SSX2 (300192), at Xp11.2. The SSX1 and SSX2 genes encode closely related proteins (81% identity) of 188 amino acids that are rich in charged amino acids. The N-terminal portion of each SSX protein exhibits homology to the Kruppel-associated box (KRAB), a transcriptional repressor domain previously found only in Kruppel-type zinc finger proteins, e.g., zinc finger protein-117 (ZNF117; 194624) and ZNF83 (194558). PCR analysis demonstrated the presence of SYT-SSX1 or SYT-SSX2 fusion transcripts in 29 of 32 synovial sarcomas examined, indicating that the detection of these hybrid transcripts by PCR may represent a useful diagnostic method. Sequence analysis demonstrated further heterogeneity in the fusion transcripts with the formation of 2 distinct SYT-SSX1 fusion junctions and 2 distinct SYT-SSX2 fusion junctions. Both the SYT-SSX1 and the SYT-SSX2 hybrid transcripts encode fusion proteins in which the C-terminal 8 amino acids of the normal SYT protein have been replaced by 78 amino acids encoded by an SSX gene. The SSX1 and SSX2 protein sequences present in these 2 fusion products have 66 of 78 amino acids in common.
Clark et al. (1994) identified the SSX1 gene at the chromosome Xp11.2 breakpoint of the synovial sarcoma-related translocation t(X;18)(p11.2;q11.2).
Chand et al. (1995) found that at least 5 copies of the SSX1 locus are clustered on the X chromosome in a region that also contains several OAT-like sequences (311240).
Stumpf (2023) mapped the SSX1 gene to chromosome Xp11.23 based on an alignment of the SSX1 sequence (GenBank BC150487) with the genomic sequence (GRCh38).
The SYT-SSX1 form of synovial sarcoma, compared to the SYT-SSX2 form, has a significantly unfavorable prognosis (Kawai et al., 1998; Ladanyi et al., 2002). This suggests that the SYT-SSX fusion genes may influence molecular mechanisms involved in tumor growth and progression and that SYT-SSX1 has a stronger influence on these mechanisms than SYT-SSX2. Xie et al. (2002) used Western blot analysis on 74 fresh, fusion variant-typed tumor samples from localized synovial sarcoma and found a significant correlation between SYT-SSX1 and high expression of cyclin A1 (CCNA1; 604036) and cyclin D1 (CCND1; 168461); P = 0.003 and P = 0.025, respectively. The data suggested that SYT-SSX may influence the cell cycle machinery, and that the more aggressive phenotype of the SYT-SSX1 variant is due to an accelerated tumor cell proliferation.
From a cohort of 536 Chinese men with infertility due to asthenoteratozoospermia (SPGFX5; 301099), Liu et al. (2023) identified 6 unrelated men with hemizygous mutations in the SSX1 gene (see, e.g., 312820.0001-312820.0003). The mutations were shown to be inherited from the unaffected mother in the 3 families for which parental DNA was studied. The mutations resulted in markedly reduced SSX1 expression of mRNA and protein in patient sperm.
Liu et al. (2023) generated Ssx1-knockdown (Ssx1-KD) animal models by microinjection of Ssx1-shRNA-containing AAV9 vectors into the seminiferous tubules via the rete testis of adult male cynomolgus monkeys and tree shrews. Testicular sections from the Ssx1-KD monkeys showed abnormal spermatogenesis with abnormal arrangements of germ cells. Sperm motility was significantly reduced, and morphologic analysis showed a higher rate of absent, short, or coiled flagella in the Ssx1-KD group than the control group. In addition, transmission electron microscopy (TEM) revealed a lack of microtubules or disorganization of outer dense fibers. In the tree shrews, testis weight was significantly reduced in the Ssx1-KD group compared to controls. Testicular sections showed impaired spermatogenesis with loss of germ cells from seminiferous tubules. Significant reductions in sperm motility and progressive motility were observed in the Ssx1-KD group, with reductions in curvilinear, straight-line, and average-path velocity as well as in amplitude of lateral head displacement and beat cross-frequency. Morphologic analysis showed absent, coiled, and angulated flagella, and TEM revealed absence of peripheral or central microtubules at the midpiece and principal piece of sperm flagella.
In a 29-year-old Chinese man (NO27) with infertility due to asthenoteratozoospermia (SPGFX5; 301099), Liu et al. (2023) identified hemizygosity for a 2-bp deletion (c.185_186del, NM_005635.3) in exon 2 of the SSX1 gene, causing a frameshift predicted to result in a premature termination codon (Gly62ValfsTer11). The mutation, which was confirmed by Sanger sequencing, was inherited from his unaffected mother and was not found in the 1000 Genomes Project or gnomAD databases. RT-qPCR and immunofluorescence studies demonstrated a dramatic reduction in the expression of SSX1 mRNA and protein in patient sperm.
In a 22-year-old Chinese man (Y1642) with infertility due to asthenoteratozoospermia (SPGFX5; 301099), Liu et al. (2023) identified hemizygosity for a c.164A-G transition (c.164A-G, NM_005635.3) in exon 3 of the SSX1 gene, resulting in a tyr55-to-cys (Y55C) substitution within the KRAB domain. The mutation, which was confirmed by Sanger sequencing, was inherited from his unaffected mother and was not found in the 1000 Genomes Project database, although it was present at very low minor allele frequency in the gnomAD database (0.0004265 in East Asians, and 0.00006142 overall). RT-qPCR and immunofluorescence studies demonstrated a dramatic reduction in the expression of SSX1 mRNA and protein in patient sperm.
In a 31-year-old Chinese man (S868) with infertility due to asthenoteratozoospermia (SPGFX5; 301099), Liu et al. (2023) identified hemizygosity for a splice site mutation (c.*4+1G-A, NM_005635.3) within the C-terminal SSXRD domain of the SSX1 gene. RT-qPCR analysis showed that the variant abrogates the consensus donor site, resulting in alternative splicing and significantly reduced expression of SSX1. The mutation, which was confirmed by Sanger sequencing, was inherited from his unaffected mother and was not found in the 1000 Genomes Project database, although it was present at very low minor allele frequency in the gnomAD database (0.0002696 in East Asians, and 0.0001902 overall). Immunofluorescence studies confirmed a dramatic reduction in SSX1 protein in patient sperm.
Chand, A., Clark, J., Cooper, C. S., Craig, I. W. Long-range organization of reiterated sequences, including the SSX1 cDNA, at the OATL1 cluster in Xp11.23. Genomics 30: 545-552, 1995. [PubMed: 8825641] [Full Text: https://doi.org/10.1006/geno.1995.1275]
Clark, J., Rocques, P. J., Crew, A. J., Gill, S., Shipley, J., Chan, A. M.-L., Gusterson, B. A., Cooper, C. S. Identification of novel genes, SYT and SSX, involved in the t(X;18)(p11.2;q11.2) translocation found in human synovial sarcoma. Nature Genet. 7: 502-508, 1994. [PubMed: 7951320] [Full Text: https://doi.org/10.1038/ng0894-502]
Crew, A. J., Clark, J., Fisher, C., Gill, S., Grimer, R., Chand, A., Shipley, J., Gusterson, B. A., Cooper, C. S. Fusion of SYT to two genes, SSX1 and SSX2, encoding proteins with homology to the Kruppel-associated box in human synovial sarcoma. EMBO J. 14: 2333-2340, 1995. [PubMed: 7539744] [Full Text: https://doi.org/10.1002/j.1460-2075.1995.tb07228.x]
Kawai, A., Woodruff, J., Healey, J. H., Brennan, M. F., Antonescu, C. R., Ladanyi, M. SYT-SSX gene fusion as a determinant of morphology and prognosis in synovial sarcoma. New Eng. J. Med. 338: 153-160, 1998. [PubMed: 9428816] [Full Text: https://doi.org/10.1056/NEJM199801153380303]
Ladanyi, M., Antonescu, C. R., Leung, D. H., Woodruff, J. M., Kawai, A., Healey, J. H., Brennan, M. F., Bridge, J. A., Neff, J. R., Barr, F. G., Goldsmith, J. D., Brooks, J. S. J., Goldblum, J. R., Ali, S. Z., Shipley, J., Cooper, C. S., Fisher, C., Skytting, B., Larsson, O. Impact of SYT-SSX fusion type on the clinical behavior of synovial sarcoma: a multi-institutional retrospective study of 243 patients. Cancer Res. 62: 135-140, 2002. [PubMed: 11782370]
Liu, C., Si, W., Tu, C., Tian, S., He, X., Wang, S., Yang, X., Yao, C., Li, C., Kherraf, Z.-E., Ye, M., Zhou, Z., and 28 others. Deficiency of primate-specific SSX1 induced asthenoteratozoospermia in infertile men and cynomolgus monkey and tree shrew models. Am. J. Hum. Genet. 110: 516-530, 2023. [PubMed: 36796361] [Full Text: https://doi.org/10.1016/j.ajhg.2023.01.016]
Stumpf, A. M. Personal Communication. Baltimore, Md. 03/16/2023.
Xie, Y., Skytting, B., Nilsson, G., Grimer, R. J., Mangham, C. D., Fisher, C., Shipley, J., Bjerkehagen, B., Myklebost, O., Larsson, O. The SYT-SSX1 fusion type of synovial sarcoma is associated with increased expression of cyclin A and D1. A link between t(X;18)(p11.2;q11.2) and the cell cycle machinery. Oncogene 21: 5791-5796, 2002. [PubMed: 12173050] [Full Text: https://doi.org/10.1038/sj.onc.1205700]