Alternative titles; symbols
HGNC Approved Gene Symbol: SOX4
Cytogenetic location: 6p22.3 Genomic coordinates (GRCh38): 6:21,593,751-21,598,619 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6p22.3 | Coffin-Siris syndrome 10 | 618506 | Autosomal dominant | 3 |
The SOX genes (so named for SRY-box) comprise a large family related by homology to the HMG-box region of the testis-determining gene SRY (480000). Four Sox genes were originally isolated from the mouse. These genes are autosomal or X-linked and can be divided into 2 subfamilies: the sequences of mouse Sox-1, -2, and -3 are almost identical in the conserved HMG-box motif, whereas Sox-4 seems to have diverged independently, showing 78% homology to the other 3 genes at the DNA level. Denny et al. (1992) identified several other members of the Sox gene family.
Farr et al. (1993) cloned and sequenced the human SOX4 gene. The open reading frame encoded a 474-amino acid protein, which included an HMG-box. The deduced amino acid sequence of the human SOX4 gene is consistent with its being a transcription factor.
SOX4 from both human and mouse was shown by van de Wetering et al. (1993) to be expressed primarily in T and pre-B lymphocyte cell lines. They also showed that the mouse Sox4 protein binds with high affinity to the (A/T)(A/T)CAAAG motif found in several T-cell specific enhancers. By transient expression of chimeric Sox4 constructs, van de Wetering et al. (1993) showed that Sox4 has separable DNA-binding and transactivation domains. The authors concluded that SOX4 is a lymphocyte-specific transcriptional activator.
Using a yeast 2-hybrid screen, Geijsen et al. (2001) identified the mouse transcriptional factor Sox4 as a binding partner for syntenin (SDCBP; 602217) but not for interleukin-5 receptor-alpha (IL5RA; 147851), which interacts with the PDZ domains of syntenin. The syntenin-Sox4 interaction occurs outside of the PDZ domains of syntenin. Luciferase reporter analysis and fluorescence microscopy showed that IL5 (147850), but not IL3 (147740), induces cytoplasmic and nuclear expression of syntenin and, in a syntenin- and cytoplasmic IL5RA-dependent manner, of Sox4. Geijsen et al. (2001) concluded that syntenin acts as an adaptor molecule in the IL5RA-mediated activation of SOX4. They also noted that mice lacking either Il5ra or Sox4 have defects in B-cell development.
Retroviral insertional mutagenesis in the mouse strains BXH2 and AKXD induces a high incidence of myeloid leukemia and B- and T-cell lymphoma, respectively. The retroviral integration sites in these tumors thus provide powerful genetic tags for the discovery of genes involved in cancer (Li et al., 1999; Hansen et al., 2000). Suzuki et al. (2002) reported a large-scale use of retroviral tagging for cancer gene discovery. Using high throughput inverse PCR, they cloned and analyzed the sequences of 884 retroviral integration sites from a tumor panel composed primarily of B-cell lymphomas. They then compared these sequences, and another 415 retroviral integration site sequences previously cloned from BXH2 myeloid leukemias and AKXD lymphomas, against the mouse genome sequence assembled by Celera. Suzuki et al. (2002) identified 152 loci that are targets of retroviral integration in more than 1 tumor (so-called common retroviral integration sites) and therefore likely to encode cancer genes. Thirty-six common retroviral integration sites encoded genes or their homologs that were known or predicted to be involved in human cancer, whereas others encoded candidate genes that had not been examined for a role in human cancer. The studies of Suzuki et al. (2002) demonstrated both the power of retroviral tagging for cancer gene discovery and the largely unrecognized complexity in mouse and presumably human cancer. Sox4 (Evi16), found in 55 tumors, was the most frequently targeted common retroviral integration site; 177 AKXD tumors and 17 NFS.V+ tumors were studied.
Lund et al. (2002) used a similar approach of insertional mutagenesis to identify loci that can participate in tumorigenesis in collaboration with loss of the Cdkn2a-encoded tumor suppressors p16ink4a and p19arf (600160).
Tavazoie et al. (2008) identified miR335 (611768) as one of a set of microRNAs for which expression is specifically lost as human breast cancer cells develop metastatic potential. Restoration of miR335 expression in malignant cells suppressed lung and bone metastasis in human cancer cells in vivo. miR335 suppresses metastasis and migration through targeting of the progenitor cell transcription factor SOX4 and extracellular matrix component tenascin C (187380).
Shim et al. (2012) identified a conserved nonexonic element (E4), located 7.3 kb downstream of the Fezf2 (607414) transcription start site, that is required for the specification of corticospinal neuron identity and connectivity. Shim et al. (2012) found that Sox4 and Sox11 (600898) functionally compete with the repressor Sox5 (604975) in the transactivation of E4. Shim et al. (2012) showed that SOX4 and SOX11 are crucial in regulating reelin (RELN; 600514) expression and the inside-out pattern of cortical layer formation, independent of E4 or Fezf2 and probably involving interactions with distinct regulatory elements. Cortex-specific double deletion of Sox4 and Sox11 led to the loss of Fezf2 expression, failed specification of corticospinal neurons and, independent of Fezf2, a reeler-like inversion of layers. Moreover, SOX4 and SOX11 have additional roles, since in mice lacking both genes, the cortex and olfactory bulb are smaller and cell death is increased. Thus, SOX4 and SOX11 have pleiotropic functions, which are probably mediated by distinct regulatory elements and downstream target genes that are involved in multiple developmental processes. Shim et al. (2012) showed evidence supporting the emergence of functional SOX-binding sites in E4 during tetrapod evolution, and their subsequent stabilization in mammals and possibly amniotes. Shim et al. (2012) concluded that SOX transcription factors converge onto a cis-acting element of Fezf2 and form critical components of a regulatory network controlling the identity and connectivity of corticospinal neurons.
Using a database of developmental expression in human brain, Zawerton et al. (2019) found that SOX4 expression is high in all brain regions during the first 2 trimesters of embryonic gestation and then decreases to a very low level by the third and fourth decades of life. SOX4 expression is higher in areas of very active neurogenesis, including the ventricular and subventricular zones. Zawerton et al. (2019) showed that SOX4 knockdown in Xenopus embryos interfered with brain and whole body development.
Gomes et al. (2020) showed that metabolic alterations that occur with age can produce a systemic environment that favors the progression and aggressiveness of tumors. Specifically, they found that methylmalonic acid (MMA) is upregulated in the serum of older people and functions as a mediator of tumor progression. Gomes et al. (2020) traced this to the ability of MMA to induce SOX4 expression and consequently to elicit transcriptional reprogramming that can endow cancer cells with aggressive properties. Thus, Gomes et al. (2020) concluded that the accumulation of MMA represents a link between aging and cancer progression.
By study of somatic cell hybrids, Farr et al. (1993) mapped the SOX4 gene to 6p, distal to the MHC region (6pter-p21.3). Fluorescence in situ hybridization (FISH) placed the gene at 6p23. Critcher et al. (1998) used FISH to refine the localization of the human SOX4 gene to 6p22.3 and to map the mouse homolog to the syntenic region of chromosome 13 (bands A3-A5).
Intellectual Developmental Disorder with Speech Delay and Dysmorphic Facies
Zawerton et al. (2019) reported 4 patients with intellectual developmental disorder with speech delay and dysmorphic facies (IDDSDF; 618506) and de novo heterozygous mutations in the SOX4 gene (184430.0001-184430.0004). All variants clustered in the highly conserved SOX family-specific HMG domain. In silico tools predicted that each variant affected a distinct structural feature of this DNA-binding domain, and functional assays demonstrated that the SOX4 proteins carrying these variants were unable to bind DNA in vitro and transactivate SOX reporter genes in cultured cells. All variants described occurred at SOX4 residues conserved through zebrafish, and missense variants at equivalent residues of other SOX family members also cause disease.
Using exome or genome sequencing in a cohort of patients with a syndromic intellectual developmental disorder, Angelozzi et al. (2022) identified 17 patients with heterozygous variants in the SOX4 gene. Using an in vitro assessment of variant function, 12 of these variants were classified as pathogenic/likely pathogenic because they disrupted SOX4 transcriptional activity, whereas the others were classified as variants of uncertain significance. Among the pathogenic/likely pathogenic variants, 7 were missense variants in the HMG DNA-binding domain and 5 were stop-gain variants (1 frameshift and 4 nonsense) (see, e.g., 184430.0005-184430.0006). When known, inheritance of the pathogenic/likely pathogenic variants was de novo or from a mosaic unaffected or a nonmosaic affected parent. The phenotype of the patients with pathogenic/likely pathogenic variants was consistent with intellectual developmental disorder with speech delay and dysmorphic facies, also called Coffin-Siris syndrome-10; however, the patients lacked the most specific features of Coffin-Siris syndrome (e.g., fifth-finger nail hypoplasia, corpus callosum agenesis, and hypertrichosis and hirsutism). Patients with variants of uncertain significance had a milder phenotype.
Somatic Mutation in Lung Cancer
Medina et al. (2009) analyzed cDNA microarrays by high-resolution comparative genome hybridization and compared DNA copy number and mRNA expression levels in lung cancer cell lines. Several amplicons had a concomitant increase in gene expression, and these regions were also found to be amplified in lung primary tumors. Within the chromosome 6p amplicon, SOX4 was overexpressed 10-fold in cells, with amplification relative to normal cells. SOX4 expression was also stronger in a fraction of lung primary tumors and lung cancer cell lines and was associated with the presence of gene amplification. Variants of SOX4 were found in lung primary tumors and cancer cell lines, including a somatic mutation that introduced a premature stop codon (ser395 to ter; S395X) at the serine-rich C-terminal domain. Although none of the variants increased the transactivation ability of SOX4, overexpression of wildtype SOX4 and of the nontruncated variants in mouse fibroblasts significantly increased the transforming ability of a weakly oncogenic RHOA (165390) mutant. The authors concluded that in some cases of lung cancer, SOX4 may be overexpressed due to gene amplification.
Sun et al. (2013) found that mice with a conditional deletion of Sox4 in hemopoietic stem cells had almost total elimination of pro-B cells in fetal livers and adult bone marrow, resulting in a severe deficiency in later stage B cells, including circulating mature B cells. Sox4-deficient pro-B cells, particularly those expressing Kit (164920), readily underwent apoptosis. Kit-expressing Sox4-deficient pro-B cells had decreased activation of the Kit downstream protein Src (190090) and lower levels of Bcl2 (151430). Restoring Bcl2 allowed both pro-B-cell survival and B-cell maturation in the absence of Sox4. Sun et al. (2013) concluded that SOX4 is required for pro-B-cell survival and that SOX4 may functionally interact with KIT and BCL2.
In an Italian boy with intellectual developmental disorder with speech delay and dysmorphic facies (IDDSDF; 618506), Zawerton et al. (2019) identified a heterozygous C-to-A transversion at nucleotide 198 (c.198C-A, NM_003107.2) of the SOX4 gene, resulting in a phenylalanine-to-leucine substitution at codon 66 (F66L). This variant occurred de novo and was not present in the gnomAD database.
In a Scottish-Hungarian boy with intellectual developmental disorder with speech delay and dysmorphic facies (IDDSDF; 618506), Zawerton et al. (2019) identified a heterozygous G-to-C transversion at nucleotide 334 (c.334G-C, NM_003107.2) of the SOX4 gene, resulting in an alanine-to-proline substitution at codon 112 (A112P). This variant occurred de novo and was not present in the gnomAD database.
In a French girl with intellectual developmental disorder with speech delay and dysmorphic facies (IDDSDF; 618506), Zawerton et al. (2019) identified a heterozygous T-to-G transversion at nucleotide 176 (c.176T-G, NM_003107.2) of the SOX4 gene, resulting in an isoleucine-to-serine substitution at codon 59 (I59S). This variant occurred de novo and was not present in the gnomAD database.
In a Scottish girl with intellectual developmental disorder with speech delay and dysmorphic facies (IDDSDF; 618506), Zawerton et al. (2019) identified a heterozygous G-to-T transversion at nucleotide 315 (c.315G-T, NM_003107.2) of the SOX4 gene, resulting in a lysine-to-asparagine substitution at codon 105 (K105N). This variant occurred de novo and was not present in the gnomAD database.
In a man (patient 21) with intellectual developmental disorder with speech delay and dysmorphic facies (IDDSDF; 618506), Angelozzi et al. (2022) identified a c.1333G-T transversion in the SOX4 gene, resulting in a glu445-to-ter (E445X) substitution. The variant was inherited from a likely mosaic unaffected father.
In an adolescent male (patient 17) with intellectual developmental disorder with speech delay and dysmorphic facies (IDDSDF; 618506), Angelozzi et al. (2022) identified an insertion/deletion mutation (c.130_133delGGCAinsCGCT) in the SOX4 gene, resulting in a frameshift (Gly44ArgfsTer2) and premature termination. The variant was inherited from an unaffected mother who was mosaic for the variant.
Angelozzi, M., Karvande, A., Molin, A. N., Ritter, A. L., Leonard, J. M. M., Savatt, J. M., Douglass, K., Myers, S. M., Grippa, M., Tolchin, D., Zackai, E., Donoghue, S., and 36 others. Consolidation of the clinical and genetic definition of a SOX4-related neurodevelopmental syndrome. J. Med. Genet. 59: 1058-1068, 2022. [PubMed: 35232796] [Full Text: https://doi.org/10.1136/jmedgenet-2021-108375]
Critcher, R., Stitson, R. N. M., Wade-Martins, R., Easty, D. J., Farr, C. J. Assignment of Sox4 to mouse chromosome 13 bands A3-A5 by fluorescence in situ hybridization; refinement of the human SOX4 location to 6p22.3 and of SOX20 to chromosome 17p12.3. Cytogenet. Cell Genet. 81: 294-295, 1998. [PubMed: 9730625] [Full Text: https://doi.org/10.1159/000015052]
Denny, P., Swift, S., Connor, F., Ashworth, A. An SRY-related gene expressed during spermatogenesis in the mouse encodes a sequence-specific DNA-binding protein. EMBO J. 11: 3705-3712, 1992. [PubMed: 1396566] [Full Text: https://doi.org/10.1002/j.1460-2075.1992.tb05455.x]
Farr, C. J., Easty, D. J., Ragoussis, J., Collignon, J., Lovell-Badge, R., Goodfellow, P. N. Characterization and mapping of the human SOX4 gene. Mammalian Genome 4: 577-584, 1993. [PubMed: 8268656] [Full Text: https://doi.org/10.1007/BF00361388]
Geijsen, N., Uings, I. J., Pals, C., Armstrong, J., McKinnon, M., Raaijmakers, J. A. M., Lammers, J.-W. J., Koenderman, L., Coffer, P. J. Cytokine-specific transcriptional regulation through an IL-5R-alpha interacting protein. Science 293: 1136-1138, 2001. [PubMed: 11498591] [Full Text: https://doi.org/10.1126/science.1059157]
Gomes, A. P., Ilter, D., Low, V., Endress, J. E., Fernandez-Garcia, J., Rosenzweig, A., Schild, T., Broekaert, D., Ahmed, A., Planque, M., Elia, I., Han, J., and 9 others. Age-induced accumulation of methylmalonic acid promotes tumour progression. Nature 585: 283-287, 2020. [PubMed: 32814897] [Full Text: https://doi.org/10.1038/s41586-020-2630-0]
Hansen, G. M., Skapura, D., Justice, M. J. Genetic profile of insertion mutations in mouse leukemias and lymphomas. Genome Res. 10: 237-243, 2000. [PubMed: 10673281] [Full Text: https://doi.org/10.1101/gr.10.2.237]
Li, J., Shen, H., Himmel, K. L., Dupuy, A. J., Largaespada, D. A., Nakamura, T., Shaughnessy, J. D., Jr., Jenkins, N. A., Copeland, N. G. Leukaemia disease genes: large-scale cloning and pathway predictions. Nature Genet. 23: 348-353, 1999. [PubMed: 10610183] [Full Text: https://doi.org/10.1038/15531]
Lund, A. H., Turner, G., Trubetskoy, A., Verhoeven, E., Wientjens, E., Hulsman, D., Russell, R., DePinho, R. A., Lenz, J., van Lohuizen, M. Genome-wide retroviral insertional tagging of genes involved in cancer in Cdkn2a-deficient mice. Nature Genet. 32: 160-165, 2002. [PubMed: 12185367] [Full Text: https://doi.org/10.1038/ng956]
Medina, P. P., Castillo, S. D., Blanco, S., Sanz-Garcia, M., Largo, C., Alvarez, S., Yokota, J., Gonzalez-Neira, A., Benitez, J., Clevers, H. C., Cigudosa, J. C., Lazo, P. A., Sanchez-Cespedes, M. The SRY-HMG box gene, SOX4, is a target of gene amplification at chromosome 6p in lung cancer. Hum. Molec. Genet. 18: 1343-1352, 2009. [PubMed: 19153074] [Full Text: https://doi.org/10.1093/hmg/ddp034]
Shim, S., Kwan, K. Y., Li, M., Lefebvre, V., Sestan, N. Cis-regulatory control of corticospinal system development and evolution. Nature 486: 74-79, 2012. [PubMed: 22678282] [Full Text: https://doi.org/10.1038/nature11094]
Sun, B., Mallampati, S., Gong, Y., Wang, D., Lefebvre, V., Sun, X. Sox4 is required for the survival of pro-B cells. J. Immun. 190: 2080-2089, 2013. [PubMed: 23345330] [Full Text: https://doi.org/10.4049/jimmunol.1202736]
Suzuki, T., Shen, H., Akagi, K., Morse, H. C., III, Malley, J. D., Naiman, D. Q., Jenkins, N. A., Copeland, N. G. New genes involved in cancer identified by retroviral tagging. Nature Genet. 32: 166-174, 2002. Note: Erratum: Nature Genet. 32: 331 only, 2002. [PubMed: 12185365] [Full Text: https://doi.org/10.1038/ng949]
Tavazoie, S. F., Alarcon, C., Oskarsson, T., Padua, D., Wang, Q., Bos, P. D., Gerald, W. L., Massague, J. Endogenous human microRNAs that suppress breast cancer metastasis. Nature 451: 147-152, 2008. [PubMed: 18185580] [Full Text: https://doi.org/10.1038/nature06487]
van de Wetering, M., Oosterwegel, M., van Norren, K., Clevers, H. Sox-4, an Sry-like HMG box protein, is a transcriptional activator is lymphocytes. EMBO J. 12: 3847-3854, 1993. [PubMed: 8404853] [Full Text: https://doi.org/10.1002/j.1460-2075.1993.tb06063.x]
Zawerton, A., Yao, B., Yeager, J. P., Pippucci, T., Haseeb, A., Smith, J. D., Wischmann, L., Kuhl, S. J., Dean, J. C. S., Pilz, D. T., Holder, S. E., Deciphering Developmental Disorders Study, University of Washington Center for Mendelian Genomics, McNeill, A., Graziano, C., Lefebvre, V. De novo SOX4 variants cause a neurodevelopmental disease associated with mild dysmorphism. Am. J. Hum. Genet. 104: 246-259, 2019. Note: Erratum: Am. J. Hum. Genet. 104: 777 only, 2019. [PubMed: 30661772] [Full Text: https://doi.org/10.1016/j.ajhg.2018.12.014]