Alternative titles; symbols
HGNC Approved Gene Symbol: SOX17
Cytogenetic location: 8q11.23 Genomic coordinates (GRCh38): 8:54,457,935-54,460,892 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 8q11.23 | Vesicoureteral reflux 3 | 613674 | Autosomal dominant | 3 |
SOX family members, such as SOX17, are transcription factors that contain a high-mobility group DNA-binding domain (HMG box) and are thought to play key roles in embryogenesis (Katoh, 2002).
By searching a human genomic database with mouse Sox17, followed by RT-PCR of mixed mRNAs from several human tissues, Katoh (2002) cloned SOX17. The deduced 414-amino acid protein contains an HMG box in its N-terminal half. SOX17 shares 41% and 43.5% identity with SOX7 (612202) and SOX18 (601618), respectively. Northern blot analysis of human tissues detected SOX17 transcripts at 2.5 and 2.2 kb in adult heart, lung, spleen, testis, ovary, and placenta, and in fetal lung and kidney. In the gastrointestinal tract, SOX17 was preferentially expressed in esophagus, stomach, and small intestine. Little to no expression was detected in other adult and fetal tissues examined. No SOX17 expression was detected in several human cancer cell lines, and no expression was detected in primary tumors derived from various tissues, except 1 case of primary cervical cancer.
Kanai et al. (1996) cloned mouse Sox17 and a splice variant from a testis cDNA library. The full-length 419-amino acid protein contains an N-terminal HMG box and a C-terminal proline- and glutamine-rich region, whereas the N-terminally truncated variant (t-Sox17) lacks most of the HMG box. Northern blot analysis detected Sox17 expression mainly in mouse lung and testis. Northern blot analysis and in situ hybridization revealed expression of full-length Sox17 in spermatogonia, and expression declined from the early pachytene spermatocyte stage onward. In contrast, t-Sox17 expression began at the pachytene spermatocyte stage and accumulated in round spermatids. SDS/PAGE revealed expression of both proteins in testis.
By EMSA and random selection assays using recombinant mouse Sox17 and t-Sox17, Kanai et al. (1996) showed that Sox17, but not t-Sox17, was a DNA-binding protein with a similar sequence specify as other SOX family members. By cotransfection experiments using a luciferase reporter gene, they found that Sox17, but not t-Sox17, could stimulate reporter gene expression.
Sinner et al. (2004) identified several direct transcriptional targets of Sox17 in Xenopus embryos, including Foxa1 (602294) and Foxa2 (600288). Beta-catenin (116806), a component of the WNT signaling pathway, physically interacted with Sox17 and potentiated its transcriptional activation of target genes.
In mouse embryonic stem cells, Liu et al. (2007) showed that cardiac myogenesis depended stringently on canonical Wnt signals acting in an early interval controlling mesoderm formation, a presumptive requirement for cardiogenesis. Sox17 expression was associated with this gastrulation-like intermediary state and was contingent on canonical Wnt signaling. RNA interference of Sox17 suppressed cardiac myogenesis selectively, as it did not impair mesoderm formation but did suppress induction of Mesp1 (608689) and Mesp2 (605195), which are transcription factors that together are pivotal to cardiac specification in primitive mesoderm.
By analyzing sequential gene expression during specification of human primordial germ cell-like cells (hPGCLCs) from human embryonic stem cells, Irie et al. (2015) identified SOX17 as the key regulator of hPGCLC specification and maintenance. Further analysis showed that SOX17 acted upstream of BLIMP1 (PRDM1; 603423) and other genes to initiate the human germ cell transcriptional network.
Walters et al. (2023) noted that 2 common variants upstream of SOX17, rs765727 and rs10958403, are associated with increased risk of pulmonary arterial hypertension (PAH; see 178600). By CRISPR inhibition and deletion analyses, Walters et al. (2023) showed that the 2 variants are located within 2 independent active enhancers of SOX17 expression in human pulmonary artery endothelial cells (hPAECs). The variants differentially bound to transcription factors, such as HOXA5 (142952) and ROR-alpha (RORA; 600825), to drive expression of SOX17. PAH-associated stimuli regulated endothelial SOX17 expression in PAH patient cells. Knockdown of SOX17 in hPAECs drove changes in downstream molecular pathways and functions relevant to PAH pathology. Moreover, analysis of the plasma proteome of PAH patients revealed that common variation in the SOX17 enhancer region led to changes in the plasma proteome with pathologically relevant functions. Loss of SOX17 caused fundamental changes in cultured hPAECs that mirrored changes observed in hPAECs of PAH patients. In addition, mice with Sox17 enhancer knockout had increased susceptibility to and severity of pulmonary hypertension. Database analysis followed by confirmation experiments identified drug compounds that could reverse some genetic changes associated with SOX17 dysfunction in hPAECs.
Katoh (2002) determined that the SOX17 gene contains 2 coding exons. Kanai et al. (1996) showed that mouse Sox17 contains a third upstream noncoding exon.
By genomic sequence analysis, Katoh (2002) mapped the SOX17 gene to chromosome 8q12-q13. Gimelli et al. (2010) noted that the SOX17 gene maps to chromosome 8q11.23.
By candidate gene sequencing of a duplicated region of chromosome 8q11-q12 in a patient with vesicoureteral reflux-3 (VUR3; 613674), Gimelli et al. (2010) identified a heterozygous mutation in the SOX17 gene (Y259N; 610928.0001). The same heterozygous mutation was found in her affected mother, in an affected mother and son from an unrelated family, and in 2 of 178 patients with sporadic occurrence of VUR. Heidet et al. (2017) called into question the pathogenicity of the Y259N variant. Gimelli et al. (2010) identified 2 additional patients with sporadic VUR were found to carry 2 different heterozygous mutations in SOX17 (610928.0002 and 610928.0003, respectively). Gimelli et al. (2010) postulated that altered levels of WNT signaling during development caused the observed congenital urinary defects, although a role for alterations in other genes regulated by SOX17 could not be excluded.
This variant, formerly titled VESICOURETERAL REFLUX 3 based on the report of Gimelli et al. (2010), has been reclassified based on the report of Heidet et al. (2017).
In 4 affected members from 2 unrelated families with vesicoureteral reflux-3 (VUR3; 613674), Gimelli et al. (2010) identified a heterozygous 775T-A transversion in exon 2 of the SOX17 gene, resulting in a tyr259-to-asn (Y259N) substitution between the HMG box and the glycine-proline-rich segment at the C-terminal end of the protein. Heterozygosity for the Y259N mutation was also found in 2 of 178 individuals with sporadic VUR and in 1 of 610 control chromosomes. Several patients had associated renal scarring, and 1 had ureter dilatation. One of the patients, who had 2 copies of the mutation due to a de novo duplication of chromosome 8q, had a more severe phenotype, with a duplicated renal pelvis and delayed psychomotor development. The affected residue, tyr259, is conserved between human, mouse, and frog, and is 1 of 4 putative tyrosine-phosphorylation sites in the protein. In vitro functional expression studies in HEK293T cells showed increased levels of the mutant SOX17 protein that was associated with increased suppression of beta-catenin (116806) signaling of the WNT pathway compared to wildtype. Gimelli et al. (2010) postulated that altered levels of WNT signaling during development caused the observed congenital urinary defects, although a role for alterations in other genes regulated by SOX17 could not be excluded.
Heidet et al. (2017) identified the Y259N variant in 1 of 204 patients with renal abnormalities. However, the variant was inherited from the unaffected father and the patient also carried missense variants in the BICC1 (614295) and DSTYK (612666) genes; both of these genes have been associated with renal abnormalities. Heidet et al. (2017) noted that the SOX17 Y259N variant was found in 1 of 181 European exomes in the ExAC database and in 82 individuals without renal abnormalities in an in-house exome database. The findings called into question whether the Y259N variant is indeed pathogenic.
In a male patient with sporadic occurrence of grade I vesicoureteral reflux-3 (VUR3; 613674) and renal scarring, Gimelli et al. (2010) identified a heterozygous mutation in the SOX17 gene, resulting in a gly178-to-cys (G178C) substitution between the HMG box and the glycine-proline-rich segment at the C-terminal end of the protein. The residue is conserved between humans, mouse, and zebrafish.
In a male patient with sporadic occurrence of grade III vesicoureteral reflux-3 (VUR3; 613674) and renal scarring, Gimelli et al. (2010) identified a heterozygous in-frame 6-bp insertion in the SOX17 gene, resulting in the addition of threonine and glutamine residues at position 17. The residues are located in a conserved N-terminal portion of the protein, but are not themselves conserved.
Gimelli, S., Caridi, G., Beri, S., McCracken, K., Bocciardi, R., Zordan, P., Dagnino, M., Fiorio, P., Murer, L., Benetti, E., Zuffardi, O., Giorda, R., Wells, J. M., Gimelli, G., Ghiggeri, G. M. Mutations in SOX17 are associated with congenital anomalies of the kidney and the urinary tract. Hum. Mutat. 31: 1352-1359, 2010. [PubMed: 20960469] [Full Text: https://doi.org/10.1002/humu.21378]
Heidet, L., Moriniere, V., Henry, C., De Tomasi, L., Reilly, M. L., Humbert, C., Alibeu, O., Fourrage, C., Bole-Feysot, C., Nitschke, P., Tores, F., Bras, M., and 13 others. Targeted exome sequencing identifies PBX1 as involved in monogenic congenital anomalies of the kidney and urinary tract. J. Am. Soc. Nephrol. 28: 2901-2914, 2017. [PubMed: 28566479] [Full Text: https://doi.org/10.1681/ASN.2017010043]
Irie, N., Weinberger, L., Tang, W. W., Kobayashi, T., Viukov, S., Manor, Y. S., Dietmann, S., Hanna, J. H., Surani, M. A. SOX17 is a critical specifier of human primordial germ cell fate. Cell 160: 253-268, 2015. [PubMed: 25543152] [Full Text: https://doi.org/10.1016/j.cell.2014.12.013]
Kanai, Y., Kanai-Azuma, M., Noce, T., Saido, T. C., Shiroishi, T., Hayashi, Y., Yazaki, K. Identification of two Sox17 messenger RNA isoforms, with and without the high mobility group box region, and their differential expression in mouse spermatogenesis. J. Cell Biol. 133: 667-681, 1996. [PubMed: 8636240] [Full Text: https://doi.org/10.1083/jcb.133.3.667]
Katoh, M. Molecular cloning and characterization of human SOX17. Int. J. Molec. Med. 9: 153-157, 2002. [PubMed: 11786926]
Liu, Y., Asakura, M., Inoue, H., Nakamura, T., Sano, M., Niu, Z., Chen, M., Schwartz, R. J., Schneider, M. D. Sox17 is essential for the specification of cardiac mesoderm in embryonic stem cells. Proc. Nat. Acad. Sci. 104: 3859-3864, 2007. [PubMed: 17360443] [Full Text: https://doi.org/10.1073/pnas.0609100104]
Sinner, D., Rankin, S., Lee, M., Zorn, A. M. Sox17 and beta-catenin cooperate to regulate the transcription of endodermal genes. Development 131: 3069-3080, 2004. [PubMed: 15163629] [Full Text: https://doi.org/10.1242/dev.01176]
Walters, R., Vasilaki, E., Aman, J., Chen, C. N., Wu, Y., Liang, O. D., Ashek, A., Dubois, O., Zhao, L., Sabrin, F., Cebola, I., Ferrer, J., Morrell, N. W., Klinger, J. R., Wilkins, M. R., Zhao, L., Rhodes, C. J. SOX17 enhancer variants disrupt transcription factor binding and enhancer inactivity drives pulmonary hypertension. Circulation 147: 1606-1621, 2023. [PubMed: 37066790] [Full Text: https://doi.org/10.1161/CIRCULATIONAHA.122.061940]