Alternative titles; symbols
HGNC Approved Gene Symbol: SOX11
Cytogenetic location: 2p25.2 Genomic coordinates (GRCh38): 2:5,692,384-5,701,385 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p25.2 | Intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism | 615866 | Autosomal dominant | 3 |
Using the partial clones of both human and mouse SOX11 genes, Jay et al. (1995) cloned and characterized the human SOX11 gene. The SOX11 sequence is strongly conserved with the chicken homolog and is related to SOX4. It contains several putative transcriptional activator or repressor domains. The authors observed that the SOX11 expression pattern is consistent with the hypothesis that this gene is important in the developing nervous system.
Jay et al. (1995) mapped the SOX11 gene to chromosome 2p25 by fluorescence in situ hybridization.
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 (184430) and Sox11 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.
Cryoelectron Microscopy
Dodonova et al. (2020) reported cryoelectron microscopy structures of the DNA-binding domains of SOX2 (184429) and its close homolog SOX11 bound to nucleosomes. The structures showed that SOX factors can bind and locally distort DNA at superhelical location 2. The factors also facilitated detachment of terminal nucleosomal DNA from the histone octamer, which increases DNA accessibility. SOX-factor binding to the nucleosome can also lead to a repositioning of the N-terminal tail of histone H4 (see 602822) that includes residue lys16. Dodonova et al. (2020) speculated that this repositioning is incompatible with higher-order nucleosome stacking, which involves contacts of the H4 tail with a neighboring nucleosome. Dodonova et al. (2020) concluded that pioneer transcription factors that maintain pluripotency can use binding energy to initiate chromatin opening, and thereby facilitate nucleosome remodeling and subsequent transcription.
SRY (480000) is the testis-determining gene located on the Y chromosome of mammals. It encodes a protein whose most striking feature is a motif of 78 amino acids conserved with respect to the DNA binding domain of the high mobility group (HMG) proteins. Jay et al. (1995) noted that more than 100 HMG box-containing proteins had been reported at that time and are classified in 2 distinct subgroups according to the sequence-specificity of the binding, the number of DNA binding domains, and phylogenetic considerations (Laudet et al., 1993). An important subgroup of HMG box-containing proteins includes SRY and SRY box-related (SOX) sequences. They contain only 1 DNA-binding domain, and they bind to DNA in a sequence-specific manner. They are all potential transcription factors implicated in the developmental control of gene expression. Degenerate PCR-based methods enabled the cloning and sequencing of a great number of new SRY-related box sequences in both vertebrates and invertebrates.
Tsurusaki et al. (2014) identified 2 de novo missense mutations in the SOX11 gene (Y116C, 600898.0001 and S60P, 600898.0002) in 2 unrelated female patients with intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism (IDDMOH; 615866), also referred to as Coffin-Siris syndrome-9 (CSS9). Both mutations occurred in the HMG domain in 2 evolutionarily conserved amino acids. Tsurusaki et al. (2014) showed that both mutations caused decreased transcriptional activation compared to wildtype. SOX11 is exclusively expressed in fetal and adult brain and in adult heart. Targeted disruption of Sox11 in mice resulted in a 23% birth weight reduction and lethality after the first postnatal week in homozygotes, due to hypoplastic lungs and ventricular septation defects. In addition, skeletal malformations, including of phalanges, and abdominal defects were observed. Physical and functional abnormalities in heterozygotes had not been described. Sox11 knockdown experiments in zebrafish showed microcephaly and brain abnormalities. Tsurusaki et al. (2014) commented that SOX11 is the downstream transcriptional factor of the PAX6 (607108)-BAF (603811) complex, highlighting the importance of the BAF complex and SOX11 transcriptional network in brain development.
In a patient with IDDMOH, Wakim et al. (2021) identified a de novo heterozygous missense mutation in the HMG domain of the SOX11 gene (I49N; 600898.0003). The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies were not performed.
In a mother and her 2 daughters with IDDMOH, Hanker et al. (2022) identified a heterozygous missense mutation in the SOX11 gene (G47S; 600898.0004). The mutation was identified by sequencing of a next-generation sequencing panel and confirmed by Sanger sequencing. Functional studies were not performed.
In 2 unrelated boys with IDDMOH, Alburaiky et al. (2022) identified de novo heterozygous missense mutations in the SOX11 gene (R100P; 600898.0005; N76D, 600898.0006).
In 2 unrelated Chinese patients with IDDMOH, Ding et al. (2022) identified de novo heterozygous mutations in the SOX11 gene (K274X; 600898.0007; Y113H, 600898.0008). The K274X mutation was predicted to result in nonsense-mediated mRNA decay. A luciferase assay using a reporter construct with a fragment of the GDF5 promoter showed that SOX11 with the Y113H mutation resulted in decreased transcriptional activity compared to wildtype.
Al-Jawahiri et al. (2022) reported heterozygous mutations in the SOX11 gene in 38 patients, including 2 sib pairs, with IDDMOH. The mutations included 25 different missense mutations, 4 truncating mutations, and 4 microdeletions. None of the mutations were present in the gnomAD database. Most of the missense mutations were located in the HMG domain. A luciferase assay using a reporter construct with the GDF5 promoter showed that SOX11 with either the A176E, Y294X or Gly384ArgfsTer14 mutation resulted in decreased transcriptional activity compared to wildtype. The transcriptional defects were more severe in the 2 protein-truncating mutations compared to the missense mutation. Methylation analysis in peripheral blood from 10 patients with IDDMOH demonstrated a hypomethylation pattern that was distinct from other BAFopathy complex epigenetic disorders.
In a Japanese girl with intellectual developmental disorder with microcephaly (IDDMOH; 615866), Tsurusaki et al. (2014) identified a c.347A-G transition in the SOX11 gene, resulting in a tyr116-to-cys (Y116C) substitution. The mutation, which occurred as a de novo event, disrupted an amino acid conserved from zebrafish to human located in the HMG domain. The mutation was not identified in the 1000 Genomes Project, Exome Variant Server, or in-house databases. The patient showed dysmorphic facial features, microcephaly, growth deficiency, hypoplastic fifth toenails, and mildly impaired intellectual development. The authors described the disorder as mild Coffin-Siris syndrome.
In a 17-year-old Indian girl with intellectual developmental disorder with microcephaly and hypogonadotropic hypogonadism (IDDMOH; 615866), Tsurusaki et al. (2014) identified a c.178T-C transition in the SOX11 gene, resulting in a ser60-to-pro (S60P) substitution. The mutation, which occurred as a de novo event, disrupted an amino acid conserved from zebrafish to human located in the HMG domain. The mutation was not identified in the 1000 Genomes Project, Exome Variant Server, or in-house databases. The patients showed dysmorphic facial features, microcephaly, growth deficiency, hypoplastic fifth toenails, and mildly impaired intellectual development. Ultrasonographic examination at age 16 years showed a hypoplastic uterus. No secondary sexual characteristics were recognized until menarche at age 17. The authors described the disorder as mild Coffin-Siris syndrome.
In a Lebanese boy with intellectual developmental disorder with microcephaly and without ocular malformations or hypogonadotropic hypogonadism (IDDMOH; 615866), Wakim et al. (2021) identified heterozygosity for a c.146T-A transition in the SOX11 gene, resulting in an ile49-to-asn (I49N) substitution at a conserved residue in the HMG domain. The mutation, which was identified by whole-exome sequencing and confirmed with Sanger sequencing, was found to be de novo. The mutation was not present in the gnomAD and 1000 Genomes databases. Functional studies were not performed.
In a mother and her 2 daughters with intellectual developmental disorder with microcephaly and ocular malformations (IDDMOH; 615866), Hanker et al. (2022) identified heterozygosity for a c.139G-A transition (c.139G-A, NM_003108.3) in the SOX11 gene, resulting in a gly47-to-ser (G47S) substitution. The mutation, which was identified by sequencing of a next-generation sequencing panel of 8 genes and confirmed by Sanger sequencing, segregated with disease in the family. Functional studies were not performed.
In a boy (patient 1) with intellectual developmental disorder with microcephaly and ocular malformations (IDDMOH; 615866), who also had bilateral cryptorchidism and micropenis, Alburaiky et al. (2022) identified de novo heterozygosity for a c.299G-C transversion (299G-C, NM_003108.3) in the SOX11 gene, resulting in an arg100-to-pro (R100P) substitution. The mutation was identified by trio whole-exome sequencing. Functional studies were not performed.
In a boy (patient 2) with intellectual developmental disorder with ocular malformations (IDDMOH; 615866), who had a head circumference on the 25th percentile at age 2 years, an underdeveloped scrotum, and palpable testes, Alburaiky et al. (2022) identified de novo heterozygosity for a c.226A-G transition (c.226A-G, NM_003108.4) in the SOX11 gene, resulting in an asn76-to-asp (N76D) substitution. The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing. Functional studies were not performed.
In a Chinese girl (patient 2) with intellectual developmental disorder with ocular malformations (IDDMOH; 615866), Ding et al. (2022) identified de novo heterozygosity for a c.820A-T transversion (c.820A-T, NM_003108.4) in the SOX11 gene, resulting in a lys274-to-ter (K274X) substitution. The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing. The mutation was predicted to result in nonsense-mediated mRNA decay. (In the article by Ding et al. (2022), the mutation is given as K142X in the abstract, but as K274X in figure 2 and the text.)
In a Chinese boy (patient 3) with intellectual developmental disorder and microcephaly (IDDMOH; 615866), Ding et al. (2022) identified a de novo heterozygous c.337T-C transition (c.337T-C, NM_003108.4) in the SOX11 gene, resulting in a tyr113-to-his (Y113H) substitution in the HMG domain. The mutation was identified by whole-exome sequencing and confirmed by Sanger sequencing. A luciferase assay using a reporter construct with a fragment of the GDF5 promoter, showed that SOX11 with the Y113H mutation resulted in decreased transcriptional activity compared to wildtype.
Al-Jawahiri, R., Foroutan, A., Kerkhof, J., McConkey, H., Levy, M., Haghshenas, S., Rooney, K., Turner, J., Shears, D., Holder, M., Lefroy, H., Castle, B., and 44 others. SOX11 variants cause a neurodevelopmental disorder with infrequent ocular malformations and hypogonadotropic hypogonadism and with distinct DNA methylation profile. Genet. Med. 24: 1261-1273, 2022. [PubMed: 35341651] [Full Text: https://doi.org/10.1016/j.gim.2022.02.013]
Alburaiky, S., Taylor, J., O'Grady, G., Thomson, G., Perry, D., England, E. M., Yap, P. Cochlear nerve deficiency in SOX11-related Coffin-Siris syndrome. Am. J. Med. Genet. 188A: 2460-2465, 2022. [PubMed: 35642566] [Full Text: https://doi.org/10.1002/ajmg.a.62851]
Ding, Y., Chen, J., Tang, Y., Chen, L. N., Yao, R. E., Yu, T., Yin, Y., Wang, X., Wang, J., Li, N. Identification and functional analysis of novel SOX11 variants in Chinese patients with Coffin-Siris syndrome 9. Front. Genet. 13: 940776, 2022. [PubMed: 35938035] [Full Text: https://doi.org/10.3389/fgene.2022.940776]
Dodonova, S. O., Zhu, F., Dienemann, C., Taipale, J., Cramer, P. Nucleosome-bound SOX2 and SOX11 structures elucidate pioneer factor function. Nature 580: 669-672, 2020. [PubMed: 32350470] [Full Text: https://doi.org/10.1038/s41586-020-2195-y]
Hanker, B., Gillessen-Kaesbach, G., Huning, I., Ludecke, H. J., Wieczorek, D. Maternal transmission of a mild Coffin-Siris syndrome phenotype caused by a SOX11 missense variant. Europ. J. Hum. Genet. 30: 126-132, 2022. [PubMed: 33785884] [Full Text: https://doi.org/10.1038/s41431-021-00865-2]
Jay, P., Goze, C., Marsollier, C., Taviaux, S., Hardelin, J.-P., Koopman, P., Berta, P. The human SOX11 gene: cloning, chromosomal assignment and tissue expression. Genomics 29: 541-545, 1995. [PubMed: 8666406] [Full Text: https://doi.org/10.1006/geno.1995.9970]
Laudet, V., Stehelin, D., Clevers, H. Ancestry and diversity of the HMG box superfamily. Nucleic Acids Res. 21: 2493-2501, 1993. [PubMed: 8506143] [Full Text: https://doi.org/10.1093/nar/21.10.2493]
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]
Tsurusaki, Y., Koshimizu, E., Ohashi, H., Phadke, S., Kou, I., Shiina, M., Suzuki, T., Okamoto, N., Imamura, S., Yamashita, M., Watanabe, S., Yoshiura, K., Kodera, H., Miyatake, S., Nakashima, M., Saitsu, H., Ogata, K., Ikegawa, S., Miyake, N., Matsumoto, N. De novo SOX11 mutations cause Coffin-Siris syndrome. Nature Commun. 5: 4011, 2014. Note: Electronic Article. [PubMed: 24886874] [Full Text: https://doi.org/10.1038/ncomms5011]
Wakim, V., Nair, P., Delague, V., Bizzari, S., Al-Ali, M. T., Castro, C., Gambarini, A., El-Hayek, S., Megarbane, A. SOX11-related syndrome: report on a new case and review. Clin. Dysmorph. 30: 44-49, 2021. [PubMed: 33086258] [Full Text: https://doi.org/10.1097/MCD.0000000000000348]