Alternative titles; symbols
HGNC Approved Gene Symbol: SOX2
SNOMEDCT: 698851003;
Cytogenetic location: 3q26.33 Genomic coordinates (GRCh38): 3:181,711,925-181,714,436 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q26.33 | Microphthalmia, syndromic 3 | 206900 | Autosomal dominant | 3 |
| Optic nerve hypoplasia and abnormalities of the central nervous system | 206900 | Autosomal dominant | 3 |
Stevanovic et al. (1994) found that the SOX2 gene encodes a 317-amino acid protein.
See SOX1 (602148) for a discussion of the SOX gene family.
Genetic analysis by Fantes et al. (2003) indicated that the single-exon SOX2 gene lies in an intron of the SOX2OT gene (616338), which is transcribed in the same orientation.
By fluorescence in situ hybridization, Stevanovic et al. (1994) assigned the SOX2 gene to chromosome 3q26.3-q27.
In developing chick spinal cord, Bylund et al. (2003) found that Sox1 (602148), Sox2, and Sox3 (313430) were coexpressed in self-renewing progenitor cells and acted to inhibit neuronal differentiation. Active repression of the Sox genes promoted neural progenitor cells to initiate differentiation prematurely. Further studies showed that the ability of the proneural transcription factor neurogenin-2 (NEUROG2; 606624) to promote neuronal differentiation was based on its ability to suppress Sox gene expression, thus showing that neurogenesis is regulated by an interplay between proneural proteins and inhibitory proteins.
Hever et al. (2006) reviewed the expression patterns and complex interactions of 3 genes associated with the development of the eye, SOX2, OTX2 (600037), and PAX6 (607108), noting that these interactions may explain the significant phenotypic overlap between mutations at these 3 loci.
Okubo et al. (2006) reported that Sox2 is required for development of taste bud sensory cells in mouse.
Induced pluripotent stem (iPS) cells can be generated from mouse fibroblasts by retrovirus-mediated introduction of 4 transcription factors, Oct3/4 (164177), Sox2, c-Myc (190080), and Klf4 (602253), and subsequent selection for Fbx15 (609093) expression (Takahashi and Yamanaka, 2006). These iPS cells, hereafter called Fbx15 iPS cells, are similar to embryonic stem (ES) cells in morphology, proliferation, and teratoma formation; however, they are different with regard to gene expression and DNA methylation patterns, and fail to produce adult chimeras. Okita et al. (2007) showed that selection for Nanog (607937) expression results in germline-competent iPS cells with increased ES cell-like gene expression and DNA methylation patterns compared with Fbx15 iPS cells. The 4 transgenes were strongly silenced in Nanog iPS cells.
Wernig et al. (2007) independently demonstrated that the transcription factors Oct4, Sox2, c-Myc, and Klf4 can induce epigenetic reprogramming of a somatic genome to an embryonic pluripotent state. In contrast to selection for Fbx15 activation (Takahashi and Yamanaka, 2006), fibroblasts that had reactivated the endogenous Oct4 (Oct4-neo) or Nanog (Nanog-neo) loci grew independently of feeder cells, expressed normal Oct4, Nanog, and Sox2 RNA and protein levels, were epigenetically identical to ES cells by a number of criteria, and were able to generate viable chimeras, contribute to the germline, and generate viable late-gestation embryos after injection into tetraploid blastocysts. Transduction of the 4 factors generated significantly more drug-resistant cells from Nanog-neo than from Oct4-neo fibroblasts, but a higher fraction of Oct4-selected cells had all the characteristics of pluripotent ES cells, suggesting that Nanog activation is a less stringent criterion for pluripotency than Oct4 activation.
Yu et al. (2007) showed that 4 factors, OCT4, SOX2, NANOG, and LIN28 (611043), are sufficient to reprogram human somatic cells to pluripotent stem cells that exhibit the essential characteristics of embryonic stem cells. These induced pluripotent human stem cells have normal karyotypes, express telomerase (see 602322) activity, express cell surface markers and genes that characterize human ES cells, and maintain the developmental potential to differentiate into advanced derivatives of all 3 primary germ layers.
Using Oct4, Sox2, Klf4, and Myc, Park et al. (2008) derived iPS cells from fetal, neonatal, and adult human primary cells, including dermal fibroblasts isolated from a skin biopsy of a healthy research subject. Human iPS cells resemble embryonic stem cells in morphology and gene expression and in the capacity to form teratomas in immune-deficient mice. Park et al. (2008) concluded that defined factors can reprogram human cells to pluripotency, and they established a method whereby patient-specific cells might be established in culture.
Masui et al. (2007) found that Sox2 was indispensable for maintaining embryonic stem (ES) cell pluripotency, since Sox2-null mouse ES cells differentiated primarily into trophectoderm-like cells. However, Sox2 was not required for activation of Oct-Sox enhancers. Microarray analysis showed that Sox2 regulates multiple transcription factors that affect Oct3/4 expression. Forced expression of Oct3/4 rescued the pluripotency of Sox2-null ES cells. Masui et al. (2007) concluded that SOX2 regulates OCT3/4 expression and maintains ES pluripotency through upstream transcription factors.
In studies in Xenopus oocytes, Danno et al. (2008) demonstrated specific binding of endogenous OTX2 and SOX2 proteins to a conserved noncoding sequence (CNS1) located approximately 2 kb upstream of the RAX (601881) promoter; reporter assays in Xenopus and HEK93T cells revealed that OTX2 and SOX2 synergistically activated RAX transcription via CNS1. GST pull-down and coimmunoprecipitation assays showed that OTX2 and SOX2 physically interacted, and this interaction was affected by missense mutations located in helices 2 and 3 of the SOX2 HMG domain (R74P, 184429.0008; L97P, 184429.0004, respectively), resulting in reduced induction of transcription via RAX CNS1. Danno et al. (2008) concluded that direct interaction between OTX2 and SOX2 proteins
Stadtfeld et al. (2008) generated mouse iPS cells from fibroblasts and liver cells by using nonintegrating adenoviruses transiently expressing Oct4, Sox2, Klf4, and c-Myc. These adenoviral iPS cells showed DNA demethylation characteristic of reprogrammed cells, expressed endogenous pluripotency genes, formed teratomas, and contributed to multiple tissues, including the germ cell line, in chimeric mice. Stadtfeld et al. (2008) concluded that their results provided strong evidence that insertional mutagenesis is not required for in vitro reprogramming.
Okita et al. (2008) independently reported the generation of mouse iPS cells without viral vectors. Repeated transfection of 2 expression plasmids, one containing the cDNAs of Oct3/4, Sox2, and Klf4 and the other containing the c-Myc cDNA, into mouse embryonic fibroblasts resulted in iPS cells without evidence of plasmid integration, which produced teratomas when transplanted into mice and contributed to adult chimeras. Okita et al. (2008) concluded that the production of virus-free iPS cells, albeit from embryonic fibroblasts, addresses a critical safety concern for potential use of iPS cells in regenerative medicine.
Hanna et al. (2009) demonstrated that the reprogramming by Oct4, Sox2, Klf4, and Myc transcription factors is a continuous stochastic process where almost all mouse donor cells eventually give rise to induced pluripotent stem (iPS) cells on continued growth and transcription factor expression. Additional inhibition of the p53 (191170)/p21 (116899) pathway or overexpression of Lin28 (611043) increased the cell division rate and resulted in an accelerated kinetics of iPS cell formation that was directly proportional to the increase in cell proliferation. In contrast, Nanog (607937) overexpression accelerated reprogramming in a predominantly cell division rate-independent manner. Quantitative analyses defined distinct cell division rate-dependent and -independent modes for accelerating the stochastic course of reprogramming, and suggested that the number of cell divisions is a key parameter driving epigenetic reprogramming to pluripotency.
Bass et al. (2009) showed that a peak of genomic amplification on chromosome 3q26.33 found in squamous cell carcinomas of the lung and esophagus contains the transcription factor gene SOX2, which is necessary for normal esophageal squamous development (Que et al., 2007) and differentiation and proliferation of basal tracheal cells (Que et al., 2009), and cooperates in induction of pluripotent stem cells, as summarized by Bass et al. (2009). Bass et al. (2009) found that SOX2 expression was required for proliferation and anchorage-independent growth of lung and esophageal cell lines, as shown by RNA interference experiments. Furthermore, ectopic expression of SOX2 in this study cooperated with FOXE1 (602617) or FGFR2 (176943) to transform immortalized tracheobronchial epithelial cells. SOX2-driven tumors showed expression of markers of both squamous differentiation and pluripotency. Bass et al. (2009) concluded that these characteristics identified SOX2 as a lineage-survival oncogene in lung and esophageal squamous cell carcinoma.
Using chromatin immunoprecipitation analysis, Yu et al. (2009) showed that mouse Zfp206 (ZSCAN10; 618365) and Oct4 reciprocally regulated expression of one another in ES cells through promoter binding. Genomewide mapping of Zfp206 targets in mouse ES cells identified Zfp206, Oct4, and Sox2 as key components of a large transcriptional regulatory network. Zfp206 selectively activated or repressed transcription of its target genes by binding to their promoters in ES cells. Many of these same genes were also regulated by Oct4 and Sox2, which colocalized and physically interacted with Zfp206 in a macromolecular complex.
Takemoto et al. (2011) demonstrated that TBX6 (602427)-dependent regulation of SOX2 determines the fate of axial stem cells. In wildtype mouse embryos, enhancer N1 of the neural primordial gene Sox2 is activated in the caudal lateral epiblast, and the cells staying in the superficial layer sustain N1 activity and activate Sox2 expression in the neural plate. In contrast, the cells destined to become mesoderm activate Tbx6 and turn off enhancer N1 before migrating into the paraxial mesoderm compartment. In Tbx6 mutant embryos, however, enhancer N1 activity persists in the paraxial mesoderm compartment, eliciting ectopic Sox2 activation and transforming the paraxial mesoderm into neural tubes. An enhancer-N1-specific deletion mutation introduced into Tbx6 mutant embryos prevented this Sox2 activation into the mesodermal compartment and subsequent development of ectopic neural tubes, indicating that Tbx6 regulates Sox2 via enhancer N1. Tbx6-dependent repression of Wnt3a (606359) in the paraxial mesodermal compartment is implicated in this regulatory process. Paraxial mesoderm-specific misexpression of a Sox2 transgene in wildtype embryos resulted in ectopic neural tube development. Thus, Takemoto et al. (2011) concluded that Tbx6 represses Sox2 by inactivating enhancer N1 to inhibit neural development, and this is an essential step for the specification of paraxial mesoderm from the axial stem cells.
Using immunoprecipitation and mass spectrometry, Engelen et al. (2011) identified Chd7 (608892) among 50 proteins that interacted with epitope-tagged Sox2 in mouse neural stem cells. Reverse immunoprecipitation and protein pull-down experiments confirmed direct interaction between Sox2 and Chd7. Knockdown of Sox2 or Chd7 via short hairpin RNA revealed an overlapping set of target genes. Sequencing of DNA bound by Sox2 and Chd7 in chromatin immunoprecipitation experiments and analysis of genes disrupted by knockdown of Sox2 or Chd7 revealed that the 2 proteins cooperated in gene activation. Engelen et al. (2011) concluded that Chd7 is an important Sox2 cofactor.
Rais et al. (2013) showed that depleting MBD3 (603573), a core member of the MBD3/NURD (nucleosome remodeling and deacetylation) repressor complex, together with OSKM (OCT4, 164177; SOX2; KLF4, 602253; and MYC, 190080) transduction and reprogramming in naive pluripotency-promoting conditions, result in deterministic and synchronized iPS cell reprogramming (nearly 100% efficiency within 7 days from mouse and human cells). Rais et al. (2013) stated that their findings uncovered a dichotomous molecular function for the reprogramming factors, serving to reactivate endogenous pluripotency networks while simultaneously directly recruiting the MBD3/NURD repressor complex that potently restrains the reactivation of OSKM downstream target genes. Subsequently, the latter interactions, which are largely depleted during early preimplantation development in vivo, lead to a stochastic and protracted reprogramming trajectory toward pluripotency in vitro. Rais et al. (2013) concluded that their deterministic reprogramming approach offered a novel platform for the dissection of molecular dynamics leading to establishing pluripotency at unprecedented flexibility and resolution.
Boumahdi et al. (2014) found that Sox2 was the most upregulated transcription factor in the cancer stem cells (CSCs) of squamous skin tumors in mice. SOX2 is absent in normal epidermis but begins to be expressed in the vast majority of mouse and human preneoplastic skin tumors, and continues to be expressed in a heterogeneous manner in invasive mouse and human squamous cell carcinomas (SCCs). In contrast to other SCCs, in which SOX2 is frequently genetically amplified, the expression of SOX2 in mouse and human skin SCCs is transcriptionally regulated. Conditional deletion of Sox2 in the mouse epidermis markedly decreases skin tumor formation after chemical-induced carcinogenesis. Using green fluorescent protein (GFP) as a reporter of Sox2 transcriptional expression (Sox2-GFP knockin mice), Boumahdi et al. (2014) showed that SOX2-expressing cells in invasive SCC are greatly enriched in tumor-propagating cells, which further increase upon serial transplantations. Lineage ablation of SOX2-expressing cells within primary benign and malignant SCCs leads to tumor regression, consistent with the critical role of SOX2-expressing cells in tumor maintenance. Conditional Sox2 deletion in preexisting skin papilloma and SCC leads to tumor regression and decreases the ability of cancer cells to be propagated upon transplantation into immunodeficient mice, supporting the essential role of SOX2 in regulating CSC function. Transcriptional profiling of SOX2-GFP-expressing CSCs and of tumor epithelial cells upon Sox2 deletion uncovered a gene network regulated by SOX2 in primary tumor cells in vivo. Chromatin immunoprecipitation identified several direct SOX2 target genes controlling tumor stemness, survival, proliferation, adhesion, invasion, and paraneoplastic syndrome. Boumahdi et al. (2014) demonstrated that SOX2, by marking and regulating the functions of skin tumor-initiating cells and CSCs, establishes a continuum between tumor initiation and progression in primary skin tumors.
Using chromatin immunoprecipitation analysis, Chassaing et al. (2016) found that Sox2 bound to a sequence within intron 15 of the mouse Ptch1 (601309) gene. Suppression of sox2 expression in zebrafish upregulated ptch1 expression and resulted in reduced eye and retina size. Knockdown of ptch1 in zebrafish also caused ocular defects, including reduced eye size. Reduced ptch1 protein in zebrafish led to overactive SHH signaling.
Zhang et al. (2019) found that human L3MBTL3 (618844) preferentially bound monomethylated lys42 in SOX2 and regulated stability of the SOX2 protein, which was sensitive to loss of both LSD1 (KDM1A; 609132) and PHF20L1, in human PA-1 teratocarcinoma cells. L3MBTL3 also interacted with DCAF5 (603812), a subunit of a CRL4 ubiquitin E3 ligase complex (see CUL4A, 603137), and cooperatively targeted methylated SOX2 for polyubiquitination-dependent proteolysis. Similarly, L3mbtl3 interacted with Sox2 and destabilized the Sox2 protein in mouse embryonic stem (ES) cells. Loss of L3mbtl3 stabilized Sox2 and restored self-renewal and pluripotency in Lsd1- or Phf20l1-knockdown mouse ES cells. Methylated Sox2 was a critical target of Lsd1 in mouse ES cells, and it appeared that methylation at both lys42 and lys117 was important for Lsd1 to maintain self-renewal and pluripotency of mouse ES cells. Induction of mouse ES cell differentiation enhanced proteolytic degradation of Sox2, which also depended on methylation of both lys42 and lys117 in Sox2.
Cryoelectron Microscopy
Dodonova et al. (2020) reported cryoelectron microscopy structures of the DNA-binding domains of SOX2 and its close homolog SOX11 (600898) 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.
Chitayat et al. (1996) and Male et al. (2002) identified constitutional deletions involving 3q27 in 3 unrelated individuals with clinical anophthalmia and microphthalmia. Driggers et al. (1999) and Kurbasic et al. (2000) reported de novo apparently balanced reciprocal translocations involving 3q27 in 2 patients with severe bilateral microphthalmia and microphthalmia/clinical anophthalmia. In the female infant reported by Driggers et al. (1999) with isolated bilateral clinical anophthalmia and a de novo t(3;11)(q27;p11.2), Fantes et al. (2003) identified a submicroscopic deletion at the 3q breakpoint. This deletion contained SOX2. Subsequent SOX2 mutation analysis identified de novo truncating mutations of SOX2 (184429.0001-184429.0003) in 4 (11%) of 35 individuals with clinical anophthalmia and other features (MCOPS3; 206900). Both eyes were affected in all cases with an identified mutation. In each case the mutation was present in heterozygous state; the parents of each individual with a mutation in SOX2 had normal SOX2 sequence.
Ragge et al. (2005) reported 4 patients with bilateral anophthalmia/microphthalmia and de novo heterozygous mutations in SOX2, including a missense mutation (184429.0004) and 3 frameshift mutations.
In a 12-year-old girl with bilateral clinical anophthalmia, Hagstrom et al. (2005) identified heterozygosity for a nonsense mutation in the SOX2 gene (184429.0005).
In an 11-month-old Mexican girl with bilateral clinical anophthalmia, mild facial dysmorphism, and developmental delay, Zenteno et al. (2005) identified heterozygosity for a 20-bp deletion in the SOX2 gene (70del20; 184429.0010).
Williamson et al. (2006) identified heterozygous loss-of-function mutations in the SOX2 gene in 3 unrelated patients with microphthalmia and esophageal atresia: the original patient reported by Rogers (1988) was found to have a 2.7-Mb deletion encompassing the SOX2 gene (184429.0006); the male infant described by Petrackova et al. (2004) was found to have a nonsense mutation (184429.0007); and a newly reported female infant was found to have a missense mutation (184429.0008).
In a female infant with bilateral clinical anophthalmos, very narrow palpebral fissures with synechiae, microcephaly, and psychomotor retardation (206900), Faivre et al. (2006) identified heterozygosity for a missense mutation in the SOX2 gene (184429.0009). The unaffected mother was also found to be heterozygous for the mutation; restriction enzyme digestion products were always lower in the mother than the proband, consistent with a lower level of mutant allele in the mother due to somatic mosaicism. An earlier pregnancy had been terminated due to severe hydrocephaly; examination of the fetus had revealed left cryptophthalmos, bilateral clinical anophthalmos, and multiple brain abnormalities.
Zenteno et al. (2006) reported male monozygotic twins with esophageal atresia and a discordant ocular phenotype in whom they identified heterozygosity for the 70del20 mutation in the SOX2 gene. One of the infants had unilateral clinical anophthalmia, whereas the other had normal ocular globes; the authors stated that this was the first reported case of SOX2 mutation causing a unilateral eye defect, and the first example of monozygotic twins discordant for anophthalmia.
Kelberman et al. (2006) screened 235 probands with congenital hypothalamo-pituitary disorders for mutations in the SOX2 gene and identified 6 patients with clinical anophthalmia or microphthalmia who had heterozygous de novo mutations (see, e.g., 184429.0001, 184429.0010, and 184429.0011), and 2 patients with bilateral optic nerve hypoplasia who had inherited heterozygous mutations (see 184429.0012 and 184429.0013). In addition to bilateral eye defects, all patients with SOX2 mutations had various associated anomalies, including anterior pituitary hypoplasia and hypogonadotropic hypogonadism, variable defects affecting the corpus callosum and mesial temporal structures, hypothalamic hamartoma, learning difficulties, sensorineural hearing loss, and esophageal atresia.
In 2 female sibs, 1 of whom was previously reported by Menetrey et al. (2002), Chassaing et al. (2007) identified heterozygosity for a 17-bp deletion in the SOX2 gene (184429.0014). The sibs were discordant for anophthalmia. Chassaing et al. (2007) concluded that SOX2 haploinsufficiency can cause a variable ocular phenotype ranging from normal eyes to anophthalmia.
Kelberman et al. (2008) ascertained 3 patients with severe eye defects and pituitary abnormalities who were screened for mutations in SOX2; one patient had been described by Male et al. (2002). All 3 harbored heterozygous SOX2 mutations: a deletion encompassing the entire gene, an intragenic deletion (70_89del; 184429.0010), and a novel nonsense mutation within the DNA binding domain that resulted in impaired transactivation. Kelberman et al. (2008) showed that human SOX2 can inhibit beta-catenin (116806)-driven reporter gene expression in vitro, whereas mutant SOX2 proteins are unable to repress this activity efficiently. They also showed that SOX2 is expressed throughout the human brain, including the developing hypothalamus, as well as the Rathke pouch, the developing anterior pituitary, and the eye. Kelberman et al. (2008) concluded that a failure to repress the Wnt (see 164820)-beta-catenin pathway could be one of the underlying pathogenic mechanisms associated with the effects of loss-of-function mutations in SOX2.
In 2 sisters with bilateral clinical anophthalmia/microphthalmia and brain anomalies, Schneider et al. (2008) identified heterozygosity for a 1-bp deletion in the SOX2 gene (184429.0015). The unaffected mother had a reduced signal for the deletion in peripheral blood and buccal cell DNA, confirming somatic mosaicism; the mutation was not found in the maternal grandparents. Schneider et al. (2008) noted that this was the third report of a family in which an unaffected mosaic mother transmitted bilateral clinical anophthalmia to 2 female offspring (see Faivre et al., 2006 and Chassaing et al., 2007).
In a 6-month-old Italian boy with clinical anophthalmia and severe microphthalmia of the right and left eyes, respectively, associated with micropenis, Pedace et al. (2009) analyzed the SOX2 gene and identified heterozygosity for a 2-bp insertion (184429.0016). No morphologic or functional anomaly of the hypothalamic-pituitary axis was detected in this patient, suggesting that SOX2 might have a direct influence on male genital development.
In a 21-year-old Japanese man with bilateral clinical anophthalmia, hypogonadotropic hypogonadism, seizures, spastic diplegia, and intellectual disability, who was negative for mutation in the HESX1 gene (601802), Numakura et al. (2010) identified heterozygosity for a nonsense mutation in SOX2 (L82X; 184429.0017). The patient also had a dental anomaly consisting of multiple supernumerary impacted teeth and persistence of deciduous teeth. Although the role of SOX2 in dental development was unknown, the authors considered the supernumerary teeth to be an extraocular symptom of the SOX2 anophthalmia syndrome.
Alatzoglou et al. (2011) reported 2 unrelated patients with bilateral clinical anophthalmia and nonprogressive pituitary tumors of early onset associated with SOX2 haploinsufficiency, due to heterozygosity for a 731-kb deletion on chromosome 3q26 encompassing SOX2 in 1 patient and a SOX2 nonsense mutation (F48X; 184429.0018) in the other. Alatzoglou et al. (2011) stated that this was the first time that SOX2 haploinsufficiency had been implicated in the generation of pituitary tumors.
In 2 sibs with microphthalmia, 1 of whom also had endocrinologic abnormalities, and their mother, who was diagnosed with idiopathic hypogonadotropic hypogonadism (see 147950) but had no other dysmorphic features and normal ophthalmologic examination, Stark et al. (2011) identified heterozygosity for a 1-bp deletion in SOX2 (184429.0019). Sequencing results in the mother suggested possible mosaicism.
Schneider et al. (2009) screened the SOX2 gene in 51 unrelated patients with clinical anophthalmia and/or microphthalmia and identified heterozygous SOX2 mutations in 10 of them, including 3 patients with the recurrent 20-bp deletion (70del20; 184429.0010). Analysis of all reported patients with SOX2 mutations suggested a potential genotype/phenotype correlation, with missense changes generally resulting in less severe ocular defects.
Dong et al. (2002) identified 2 allelic mouse mutants, 'light coat and circling' (Lcc) and 'yellow submarine' (Ysb), that show hearing and balance impairment. Lcc/Lcc mice are completely deaf, whereas Ysb/Ysb mice are severely hearing impaired. Kiernan et al. (2005) reported that inner ears of Lcc/Lcc mice failed to establish a prosensory domain and neither hair cells nor supporting cells differentiated, resulting in a severe inner ear malformation, whereas the sensory epithelium of Ysb/Ysb mice showed abnormal development with disorganized and fewer hair cells. These phenotypes are due to the absence (in Lcc mutants) or reduced expression (in Ysb mutants) of the transcription factor Sox2, specifically within the developing inner ear. Kiernan et al. (2005) showed that Sox2 continues to be expressed in the inner ears of mice lacking Math1 (601461), a gene essential for hair cell differentiation, whereas Math1 expression is absent in Lcc mutants, suggesting that Sox2 acts upstream of Math1.
Ferri et al. (2004) developed mice that lacked one Sox2 allele and had a deletion in the other Sox2 allele that removed a neural cell-specific enhancer. These compound heterozygotes were born with cerebral malformations and neural cell pathology, and they showed proliferative defects in adult neural stem/progenitor cells.
Taranova et al. (2006) generated a gene-dosage allelic series of Sox2 mutations in mice. The mutant mice had a range of eye phenotypes, the severity of which directly related to the level of Sox2 expression in neural retinal progenitor cells. Retinal progenitor cells with conditionally ablated Sox2 lost competence both to proliferate and to differentiate terminally. Mice with less than 40% of normal Sox2 expression in the neural retina showed variable microphthalmia as a result of aberrant neural progenitor differentiation. In addition, Taranova et al. (2006) found that Sox2 regulated Notch1 (190198) signaling in a concentration-dependent manner in retinal progenitor cells. They concluded that precise regulation of SOX2 dosage is critical for temporal and spatial regulation of retinal progenitor cell differentiation.
Kelberman et al. (2006) generated mice heterozygous for a targeted disruption of Sox2. The mutant mice did not manifest eye defects but showed abnormal anterior pituitary development with reduced levels of growth hormone, luteinizing hormone, and thyroid-stimulating hormone, and mutant males had impaired fertility. Kelberman et al. (2006) concluded that Sox2 is necessary for the normal development of the hypothalamo-pituitary and reproductive axes in mice.
Tay et al. (2008) demonstrated the existence of many naturally occurring miRNA targets in the amino acid coding sequences of the mouse Nanog (607937), Oct4 (164177), and Sox2 genes. Some of the mouse targets analyzed do not contain the miRNA seed, whereas others span exon-exon junctions or are not conserved in the human and rhesus genomes. MiRNA134 (610164), miRNA296 (610945), and miRNA470, upregulated on retinoic acid-induced differentiation of mouse embryonic stem cells, target the coding sequence of each transcription factor in various combinations, leading to transcriptional and morphologic changes characteristic of differentiating mouse embryonic stem cells, and resulting in a new phenotype. Silent mutations at the predicted targets abolished miRNA activity, prevented the downregulation of the corresponding genes, and delayed the induced phenotype. Tay et al. (2008) concluded that their findings demonstrated the abundance of coding sequence-located miRNA targets, some of which can be species-specific, and supported an augmented model whereby animal miRNAs exercise their control on mRNAs through targets that can reside beyond the 3-prime untranslated region.
In 2 male patients with bilateral clinical anophthalmia and associated features (MCOPS3; 206900), Fantes et al. (2003) identified heterozygosity for a de novo 529C-T transition in the SOX2 gene resulting in a terminating change, gln177 to stop (Q177X). One of the affected males had a small remnant at the orbital apex bilaterally; he also had microcephaly, cryptorchidism, micropenis, sensorineural deafness, and learning difficulties (possibly due to bacterial meningitis). The other patient had hypospadias, hypotonia, delayed motor development, and febrile convulsions.
In an 18-year-old male with bilateral clinical anophthalmia, Kelberman et al. (2006) identified heterozygosity for a de novo Q177X mutation in the SOX2 gene. In infancy the patient was noted to have mild facial dysmorphism with a prominent forehead and abnormal nares and philtrum, micropenis with bilateral cryptorchidism, neurodevelopmental delay, and hypotonia with abnormal movements. Short stature led to endocrinologic evaluation at age 9 that ultimately resulted in a diagnosis of gonadotropin deficiency with complete hypogonadotropic hypogonadism.
In a female patient with clinical anophthalmia of the right eye, microphthalmia and sclerocornea of the left eye (MCOPS3; 206900), and proximal myopathy, Fantes et al. (2003) found a de novo heterozygous glu93-to-stop (E93X) mutation of the SOX2 gene. Intelligence was normal in this patient.
In a female patient with clinical anophthalmia of the right eye, microphthalmia with persistent pupillary membrane of the left eye, spastic diplegia, learning difficulties, and seizures (MCOPS3; 206900), Fantes et al. (2003) identified a de novo heterozygous ser83-to-stop (S83X) mutation in the SOX2 gene.
In a 6-year-old girl with microphthalmia, sclerocornea, and coloboma of the right eye, sclerocornea and aphakia of the left eye, a mild learning disability, and seizures (MCOPS3; 206900), Ragge et al. (2005) identified heterozygosity for a de novo 290T-C transition in the SOX2 gene, resulting in a leu97-to-pro (L97P) substitution in the highly conserved HMG box of the protein. The mutation is predicted to cause loss of function.
In studies in Xenopus cells, Danno et al. (2008) demonstrated that the L97P mutation affected physical interaction between the SOX2 and OTX2 (600037) proteins and reduced induction of transcription of RAX (601881), another gene involved in eye development. Wildtype SOX2 potently bound to a conserved noncoding sequence 2 kb upstream of the RAX promoter, but L97P-mutant SOX2 did not.
In a 12-year-old girl with bilateral clinical anophthalmia, mild bilateral sensorineural hearing loss, and global developmental delay (MCOPS3; 206900), Hagstrom et al. (2005) identified heterozygosity for a de novo 463C-T transition in the SOX2 gene, predicting a gln155-to-ter (Q155X) substitution.
In a patient with bilateral clinical anophthalmia, esophageal atresia, and glanular hypospadias (MCOPS3; 206900), originally reported by Rogers (1988), Williamson et al. (2006) identified heterozygosity for a 2.7-Mb deletion encompassing the SOX2 gene, extending from RP11-145M9 to RP11-296J4 and associated with a cryptic translocation t(3,7)(q28;p21.3). The deletion and translocation breakpoints on chromosome 3q are more than 8.6 Mb apart, and both chromosomal rearrangements occurred de novo.
In a male infant with bilateral clinical anophthalmia, esophageal atresia, duplication of the left kidney, and significant psychomotor delay (MCOPS3; 206900), originally reported by Petrackova et al. (2004), Williamson et al. (2006) identified heterozygosity for a 163C-T transition in the SOX2 gene, resulting in a gln55-to-ter (Q55X) substitution with production of a protein truncated within the HMG domain and therefore with no DNA-binding or transactivation activity. The mutation was not found in either parent.
In a female infant with extreme bilateral microphthalmia and esophageal atresia (MCOPS3; 206900), Williamson et al. (2006) identified heterozygosity for a 221G-C transversion, resulting in an arg74-to-pro (R74P) substitution. The authors noted that R74 is located within the HMG domain and is invariant in all known SOX2 genes and is conserved in all human SOX group B genes. The mutation was not found in either parent.
In studies in Xenopus cells, Danno et al. (2008) demonstrated that the R74P mutation affected physical interaction between the SOX2 and OTX2 (600037) proteins and reduced induction of transcription of RAX (601881), another gene involved in eye development. Wildtype SOX2 potently bound to a conserved noncoding sequence 2 kb upstream of the RAX promoter, but R74P-mutant SOX2 did not.
In a female infant with bilateral clinical anophthalmos, very narrow palpebral fissures with synechiae, microcephaly, and psychomotor retardation (MCOPS3; 206900), Faivre et al. (2006) identified heterozygosity for a 138T-G transversion in the SOX2 gene, resulting in an asn46-to-lys (N46K) substitution predicted to alter a critical residue in the HMG box domain. The unaffected mother was also found to be heterozygous for the mutation; restriction enzyme digestion products were always lower in the mother than the proband, consistent with a lower level of mutant allele in the mother due to somatic mosaicism. An earlier pregnancy had been terminated due to severe hydrocephaly; examination of the fetus had revealed left cryptophthalmos, bilateral clinical anophthalmos, and multiple brain abnormalities.
In an 11-month-old Mexican girl with bilateral clinical anophthalmia, mild facial dysmorphism, and developmental delay (MCOPS3; 206900), Zenteno et al. (2005) identified heterozygosity for a 20-bp deletion at nucleotide 70 (70del20) of the SOX2 gene, resulting in a frameshift upstream of the HMG box and a premature termination signal 65 codons downstream. The authors noted that the deleted segment was flanked by the short GGCGGC repeat sequence, suggesting slipped-strand misrepairing as the origin of the deletion.
In male monozygotic twins with ocular defects, esophageal atresia, and genital abnormalities, Zenteno et al. (2006) identified heterozygosity for the 70del20 mutation in the SOX2 gene. Both infants had tracheoesophageal fistula, but otherwise exhibited a discordant phenotype: 1 twin had left clinical anophthalmia and bilateral cryptorchidism, whereas the other had normal globes, narrowing of the right palpebral fissure, and no genital abnormalities. The authors stated that this was the first reported case of SOX2 mutation causing a unilateral eye defect and the first example of monozygotic twins discordant for anophthalmia.
In a 22-year-old female with left clinical anophthalmia and right microphthalmia, learning difficulties, and primary amenorrhea, Kelberman et al. (2006) identified heterozygosity for a de novo 70del20 mutation in the SOX2 gene. Brain MRI revealed an abnormal hypoplastic pituitary gland in a small sella turcica with an absent left eye and optic nerve. Functional analysis of the mutant protein revealed impaired nuclear localization, DNA binding, and transcriptional activation.
Kelberman et al. (2008) identified this deletion (70_89del) in a 14.5-year-old girl who presented with bilateral anophthalmia at birth. Brain MRI showed an arachnoid cyst in the suprasellar area, with right deflection of the pituitary pedunculus. She later developed gonadotropin deficiency with low basal gonadotropin concentrations and poor response to gonadotropin-releasing hormone (GNRH; 152760) stimulation. There was no evidence of learning difficulties.
In a girl and 2 boys with bilateral clinical anophthalmia or severe microphthalmia, Schneider et al. (2009) identified the 70del20 mutation in the SOX2 gene. All 3 patients had developmental delay. Neuroimaging showed a hamartoma of the tuber cinereum in the 2-year-old girl, but was normal in the other 2 patients; none had pituitary anomalies. The 2 boys displayed genital anomalies, including micropenis, cryptorchidism, and foreskin adhesion. Other features seen in the 2 boys included a heart murmur in 1 patient and 2-3 toe syndactyly, febrile seizures, and mild pectus excavatum in the other. The girl had a half-sister with unilateral clinical anophthalmia and mental retardation.
In a 13-year-old girl with bilateral clinical anophthalmia, learning difficulties, spastic diplegia, and a history of esophageal atresia (MCOPS3; 206900), previously reported by Morini et al. (2005), Kelberman et al. (2006) identified heterozygosity for a 1-bp insertion (60insG) in the SOX2 gene, predicted to result in a truncation at codon 95 that completely removes the HMG box. Pelvic ultrasound revealed small ovaries and an infantile uterus, suggesting a diagnosis of hypogonadotropic hypogonadism. Brain MRI revealed hippocampal abnormalities with anterior pituitary hypoplasia, hypothalamic hamartoma, small corpus callosum, generalized reduction of white matter, and absent optic nerves. Functional analysis of the mutant protein revealed impaired nuclear localization, DNA binding, and transcriptional activation.
In an 11-year-old girl with roving eye movements, severe visual impairment, bilateral optic nerve hypoplasia, developmental delay, short stature, and spastic diplegia (see 206900), Kelberman et al. (2006) identified heterozygosity for a 389G-C transversion in the SOX2 gene, resulting in a gly130-to-ala (G130A) substitution. Brain MRI revealed an absent septum pellucidum, bilateral optic nerve hypoplasia, bilateral schizencephaly, right porencephalic cyst, and normal anterior and posterior pituitary. A brother died at age 11 years with hydranencephaly. The mutation was inherited from her phenotypically normal father; the mutation was not found in 100 control chromosomes.
In a 2-year-old girl who was hypoglycemic at birth and noted to have roving eye movements and bilateral optic nerve hypoplasia (see 206900), Kelberman et al. (2006) identified heterozygosity for a 571G-A transition in the SOX2 gene, resulting in an ala191-to-thr (A191T) substitution. Brain MRI revealed an absent septum pellucidum, small optic chiasm, absent infundibulum, severe hypoplasia of the anterior pituitary, and an ectopic or undescended posterior pituitary. Endocrine evaluation revealed deficiencies in growth hormone, thyroid stimulating hormone, and adrenocorticotropic hormone. The mutation was inherited from her phenotypically normal father; the mutation was not found in 100 control chromosomes.
In 2 female sibs with syndromid microphthalmia (MCOPS3; 206900), 1 of whom was previously reported by Menetrey et al. (2002), Chassaing et al. (2007) identified heterozygosity for a 17-bp deletion (70del17) in the SOX2 gene, predicted to cause a frameshift resulting in a premature termination signal at codon 66. The first sib had bilateral anophthalmia and esophageal atresia. During the mother's subsequent pregnancy, the fetus showed severe and progressive triventricular hydrocephalus on ultrasound, and the pregnancy was interrupted. Autopsy showed stenosis of the Sylvian aqueduct, and hypoplasia of the corpus callosum, but age-appropriate ocular length and normal external and microscopic ocular examination. The mother was found to have germinal mosaicism for the mutation, estimated at approximately 3%.
In 2 sisters with bilateral clinical anophthalmia/microphthalmia and brain anomalies (MCOPS3; 206900), Schneider et al. (2008) identified heterozygosity for a 1-bp deletion (551delC) in the SOX2 gene, predicted to cause a frameshift and premature termination resulting in a nonfunctional protein. The unaffected mother, who had 2 healthy older children, was found to have a reduced signal for the deletion in peripheral blood and buccal cell DNA, confirming somatic mosaicism; the mutation was not found in the maternal grandparents.
In a 6-month-old Italian boy with clinical anophthalmia and severe microphthalmia of the right and left eyes, respectively, associated with micropenis (MCOPS3; 206900), Pedace et al. (2009) identified heterozygosity for a de novo 2-bp insertion (60insGG) in the SOX2 gene, causing a frameshift resulting in a premature termination codon that was predicted to cause loss of 94% of the encoded protein. The mutation was not detected in the patient's unaffected second-cousin parents or in his unaffected dizygotic twin, and was not found in 200 control chromosomes. Repeated endocrinologic evaluation and brain MRI in this patient did not reveal any morphologic or functional anomaly of the hypothalamic-pituitary axis.
In a 21-year-old Japanese man with bilateral clinical anophthalmia, hypogonadotropic hypogonadism, seizures, spastic diplegia, intellectual disability, and dental anomalies including multiple supernumerary impacted teeth, Numakura et al. (2010) identified heterozygosity for a 245T-A transversion in the SOX2 gene, resulting in a leu82-to-ter (L82X) substitution, predicted to produce a protein truncated within the HMG domain that would lack DNA-binding and transactivation activity. The patient's mother did not carry the mutation; DNA from the father was not available.
In a male infant born with bilateral clinical anophthalmia who was referred for evaluation of micropenis (MCOPS3; 206900), Alatzoglou et al. (2011) identified heterozygosity for a 143TC-AA change in the SOX2 gene, resulting in a phe48-to-ter (F48X) substitution that was predicted to generate a truncated protein lacking most of the HMG domain and the C-terminal domain. DNA from the parents was unavailable. Immunostaining of transfected HEK293T cells showed mainly cytoplasmic localization of the mutant compared to the nuclear localization of wildtype protein, and luciferase expression studies showed only a 1.59-fold activation of the basal reporter activity with the F48X mutant compared to a 3.31-fold increase with wildtype. In addition, the mutant failed to suppress beta-catenin (116806) transcriptional activity in vitro, whereas it was significantly reduced by wildtype SOX2. Examination at 17 months of age revealed a stretched penile length of 2.5 cm and a hypoplastic scrotum with testes of 0.5 to 1.0 ml palpable high in the scrotal sacs. Endocrine evaluation showed low IGF1 (147440), and the testosterone response to a 3-week hCG test was consistent with hypogonadotropic hypogonadism. MRI at 17 months of age revealed a pituitary mass with a cystic component extending to the suprasellar area, and review of an MRI from the neonatal period, which was thought to have been normal apart from absent prechiasmatic optic nerves, showed that the mass had been present at that stage. A follow-up MRI at 32 months of age demonstrated only a modest increase in size of the mass.
In an 8-year-old boy with bilateral clinical anophthalmia and endocrinologic abnormalities (MCOPS3; 206900) and his sister who had only unilateral microphthalmia, Stark et al. (2011) identified heterozygosity for a 1-bp deletion (837delC) in the SOX2 gene, predicted to cause a frameshift and addition of 90 abnormal C-terminal residues (Gly208AlafsTer91). The boy had transient growth and growth hormone disturbances in infancy, but was not dysmorphic and had descended testes with a normal phallus; subsequently his growth normalized and pituitary function was normal on yearly monitoring. MRI of the brain at 1 year of age showed no eye remnants and absent optic nerves, an intact corpus callosum and a normal pituitary, but a dysplastic right hippocampus. His 8-month-old sister had left microphthalmia and a large left retinal coloboma, but no associated anomalies or dysmorphic features. Their mother, who had been evaluated at 18 years of age for primary amenorrhea and limited development of secondary sexual characteristics and was diagnosed with isolated hypogonadotropic hypogonadism, had a normal sense of smell, no dysmorphism, and a normal ophthalmologic examination. Sequencing results from the mother's lymphocyte DNA showed the presence of the mutation but at lower levels compared to her children, suggesting possible mosaicism. The unaffected father's sequencing results were normal.
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