Alternative titles; symbols
HGNC Approved Gene Symbol: SOX3
SNOMEDCT: 237683004;
Cytogenetic location: Xq27.1 Genomic coordinates (GRCh38): X:140,502,985-140,505,069 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| Xq27.1 | Intellectual developmental disorder, X-linked, with isolated growth hormone deficiency | 300123 | 3 | |
| Panhypopituitarism, X-linked | 312000 | X-linked | 3 |
The mammalian genome contains a family of genes that are related to SRY (480000), the testis-determining gene. The homology is restricted to the region of SRY that encodes a DNA-binding motif of the HMG-box class (the DNA-binding domain is called HMG for 'high mobility group'). These genes have been named SOX, for SRY-related HMG-box (see SOX1; 602148).
Stevanovic et al. (1993) cloned and characterized SOX3. A reverse transcription coupled with PCR (RT-PCR) was used to amplify SRY-related transcripts expressed during embryogenesis in human fetal spinal cord. Inspection of fragments detected by one of them showed a difference between males and females, suggesting a SOX gene located on the X chromosome. Isolation and sequencing of the gene showed 97.2% similarity to the protein encoded by the mouse Sox3 gene which is also located on the X chromosome. The RACE (rapid amplification of complementary DNA ends) method was used to define the 3-prime end of the transcript and to confirm that the SOX3 gene is expressed. Using the sensitive RT-PCR assay, SOX3 gene transcripts were detected in several fetal tissues.
Collignon et al. (1996) determined that the SOX3 gene consists of a single exon.
By use of a panel of somatic cell hybrids containing different terminal deletions of the long arm of the X chromosome, Stevanovic et al. (1993) mapped the SOX3 gene to Xq26-q27. SOX3 appeared to map to a region of about 5 Mb between DXS51 and DXS98.
Foster and Graves (1994) identified a sequence on the marsupial X chromosome that shares homology with SRY and shows near-identity with the mouse and human SOX3 gene (formerly called a3), the SOX gene most closely related to SRY. Foster and Graves (1994) suggested that the highly conserved X chromosome-linked SOX3 represents the ancestral SOX gene from which the sex-determining SRY gene was derived.
In therian mammals (placentals and marsupials), sex is determined by an XX female:XY male system in which the SRY gene on the Y chromosome affects male determination. Birds have a ZW female:ZZ male system with no homology with mammalian sex chromosomes. In birds, dosage of a Z-borne gene, possibly Dmrt1 (602424), affects male determination. Platypus employ a sex-determining system of 5 X and 5 Y chromosomes. Females have 2 copies of the 5 Xs, and males have 5X and 5Y chromosomes, which form an alternating XY chain during male meiosis. Veyrunes et al. (2008) found no homology between the 10 platypus sex chromosomes and the ancestral therian X chromosome, which is homologous to platypus chromosome 6. Orthologs of genes in the conserved region of human X (including SOX3, the gene from which SRY evolved) all map to platypus chromosome 6, which therefore represents the ancestral autosome from which the therian X and Y pair derived. The platypus X chromosomes have substantial homology with the bird Z chromosome (including DMRT1), and to segments syntenic with this region in the human genome. Veyrunes et al. (2008) suggested that the therian X and Y chromosomes (including the SRY gene) evolved from an autosomal pair after the divergence of monotremes only 166 million years ago.
In developing chick spinal cord, Bylund et al. (2003) found that Sox1, Sox2 (184429), and Sox3 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.
On the basis of sequence homology, SOX3 is closely related to SOX1 (602148) and SOX2 (184429), and the products of all 3 genes belong to the SOXB1 subfamily and are expressed throughout the developing central nervous system (CNS) (Collignon et al., 1996). All 3 proteins contain an HMG box.
Intellectual Developmental Disorder, X-linked, with Isolated Growth Hormone Deficiency
In affected members of a family with mental retardation and isolated growth hormone deficiency (see 300123) reported by Hamel et al. (1996), Laumonnier et al. (2002) identified an in-frame duplication of 33 bp encoding 11 alanines in a polyalanine tract of the SOX3 gene (313430.0001). The expression pattern during neural and pituitary development suggested that dysfunction of the SOX3 gene caused by the polyalanine expansion might disturb transcription pathways and the regulation of genes involved in cellular processes and functions required for cognitive and pituitary development.
Hypopituitarism, X-Linked
Solomon et al. (2004) determined that all cases of X-linked hypopituitarism from 5 unrelated families with Xq duplications contained duplications in the SOX3 gene, suggesting that increased dosage of SOX3 results in perturbation of pituitary and hypothalamic development. Three of the families had been reported by Lagerstrom-Fermer et al. (1997), Hol et al. (2000), and Zipf et al. (1977). Solomon et al. (2007) reported that they were unable to replicate the findings of an Xq26-q27 duplication in 3 families with X-linked hypopituitarism without mental retardation studied by Solomon et al. (2004), including the family reported by Zipf et al. (1977). The duplication was confirmed in the families with X-linked hypopituitarism and mental retardation (300123) reported by Lagerstrom-Fermer et al. (1997) and Hol et al. (2000).
In affected members of 2 unrelated families with X-linked panhypopituitarism (312000) and MRI evidence of structural pituitary abnormalities, including anterior pituitary hypoplasia, an ectopic posterior pituitary, and absent infundibulum, Woods et al. (2005) identified duplications in the SOX3 gene (313430.0002 and 313430.0003, respectively). The findings implicated SOX3 in the development of the midline forebrain structures. None of the patients had mental retardation. The authors also identified a novel polymorphism, 127G-A (ala43 to thr), in a child from Ghana with sporadic combined pituitary hormone deficiency. This polymorphism was identified in heterozygous state in 3 of 19 normal controls from an Afro-Caribbean background. Woods et al. (2005) concluded that both over- and underdosage of SOX3 are associated with variable panhypopituitarism, but not necessarily mental retardation.
46,XX Sex Reversal 3
Sutton et al. (2011) screened a cohort of 16 SRY (480000)-negative 46,XX male patients (300833) for copy number variation (CNV) and identified rearrangements encompassing or in close proximity to the SOX3 gene in 3 patients. Patient 'A' had 2 microduplications of approximately 123 kb and 85 kb, with the larger spanning the entire SOX3 gene. FISH analysis was consistent with tandem duplication, and the centromeric duplication was approximately 70 kb downstream from the SOX3 gene, very close to a previously described deletion/insertion breakpoint in individuals with X-linked hypoparathyroidism (Bowl et al., 2005), postulated to have a positional effect on SOX3 expression. Patient 'B' had a single 343-kb microdeletion immediately upstream of SOX3, suggesting that altered regulation rather than increased dosage of SOX3 is the cause of XX male sex reversal. Patient 'C,' who displayed a more complex phenotype including microcephaly, developmental delay, and growth retardation, had an approximately 6-Mb duplication that encompassed SOX3 and at least 18 additional distally located genes. The proximal breakpoint fell within the SOX3 regulatory region, close to the proximal SOX3 duplication breakpoint in the first patient. Transactivation assays using a human SOX9 (608160) testis enhancer sequence demonstrated approximately 10-fold and 5-fold activation by SOX3 and SRY, respectively, and activation levels were further enhanced in the presence of exogenous SF1 (NR5A1; 184757), suggesting synergistic activation. Sutton et al. (2011) stated that these data, together with their studies in transgenic mice (see ANIMAL MODEL), suggested that SOX3 and SRY are functionally interchangeable in sex determination and support the notion that SRY evolved from SOX3 via a regulatory mutation that led to its de novo expression in the early gonad.
Hypoparathyroidism, X-Linked
In studies in the affected members of a Missouri family with X-linked hypoparathyroidism (HYPX; 307700), originally reported by Peden (1960), Bowl et al. (2005) undertook a detailed characterization of the genomic region containing the HYPX locus by combined analysis of single-nucleotide polymorphisms and sequence-tagged sites. This identified a 23- to 25-kb deletion, which did not contain genes. However, DNA fiber-FISH and pulsed-field gel electrophoresis revealed an approximately 340-kb insertion that replaced the deleted fragment. Use of flow-sorted X chromosome-specific libraries and DNA sequence analyses revealed that the telomeric and centromeric breakpoints on X were, respectively, approximately 67 kb downstream of SOX3 and within a repetitive sequence. Use of a monochromosomal somatic cell hybrid panel and metaphase-FISH mapping demonstrated that the insertion originated from 2p25 and contained a segment of the SNTG2 gene (608715) that lacked an open reading frame. However, the deletion-insertion, which represents a novel abnormality causing hypoparathyroidism, could result in a position effect on SOX3 expression. Indeed, Sox3 expression was demonstrated, by in situ hybridization, in the developing parathyroid tissue of mouse embryos between 10.5 and 15.5 days postcoitum. Thus, the results indicated a likely role for SOX3 in the embryonic development of the parathyroid glands.
Stankiewicz et al. (2005) reported a family in which 4 women had short stature, speech defects with stuttering and dyslalia, and variable hearing impairment associated with a 7.5-Mb duplication of Xq26.2-q27.1 that encompassed or disrupted the SOX3 gene. A significant proportion of lymphocytes in 2 patients showed activation of the duplicated X chromosome. Stankiewicz et al. (2005) suggested that a dosage effect of SOX3 may be responsible for the speech disorder.
Bleyl et al. (2007) reported a mother and son with anterior segment eye abnormalities and an unusual skeletal phenotype overlapping the SHOX (312865)-related skeletal dysplasias. The mother, who was previously described by Kivlin et al. (1993), was found to have a 46,X,inv(X)(p22.3q27) pericentric inversion of the X chromosome; her son had a resultant 46,Y,rec(X)dup(Xq)inv(X)(p22.3q27) recombinant X chromosome. Array CGH mapping localized the Xq27.1 breakpoint to an interval approximately 90 kb 3-prime of the SOX3 gene; noting that no other genes lie within 350 kb, the authors suggested that misexpressed SOX3 may have led to the anterior chamber abnormalities in these patients. The Xp22.33 breakpoint was 30 to 68 kb 5-prime of the SHOX gene, which was presumably responsible for the skeletal phenotype.
Weiss et al. (2003) found that female Sox3-null mice developed ovaries but had excess follicular atresia, ovulation of defective oocytes, and severely reduced fertility. Pituitary and uterine functions were normal. Hemizygous male null mice developed testes but were hypogonadal. Testis weight was reduced, and there was extensive Sertoli cell vacuolization, loss of germ cells, reduced sperm counts, and disruption of the seminiferous tubules. Null mice of both sexes showed no overt behavioral deficits and normal growth hormone (139250) expression. Sox3-null mice consistently showed overgrowth and misalignment of the front teeth, and some mice had low body weight. Weiss et al. (2003) concluded that Sox3 is not required for gonadal determination in mice, but is important for normal oocyte development and male testis differentiation and gametogenesis.
In mouse embryos, Solomon et al. (2004) demonstrated that the Sox3 gene was expressed at 11.5 and 12.5 days after conception in the infundibulum of the developing pituitary and the presumptive hypothalamus.
The pituitary develops from the interaction of the infundibulum, a region of the ventral diencephalon, and Rathke pouch, a derivative of oral ectoderm. Postnatally, its secretory functions are controlled by hypothalamic neurons, which also derive from the ventral diencephalon. To investigate the mechanism by which mutations in the single-exon gene SOX3 result in hypopituitarism and mental retardation, Rizzoti et al. (2004) produced deletion of the Sox3 gene in mice and found that the deletion resulted in defects of pituitary function and of specific CNS midline structures. Cells in the ventral diencephalon, where Sox3 is usually highly expressed, had altered properties in mutant embryos, leading to abnormal development of the Rathke pouch, which does not express the gene. Pituitary and hypothalamic defects persisted postnatally, and SOX3 may also function in a subset of hypothalamic neurons.
In studies to identify the genetic abnormality underlying X-linked recessive hypoparathyroidism (307700), Bowl et al. (2005) examined Sox3 expression in mouse embryos by in situ hybridization. They demonstrated expression in the developing parathyroid tissue of mouse embryos between 10.5 and 15.5 days postcoitum. Thus, the results indicated a likely role for SOX3 in the embryonic development of the parathyroid glands.
Sutton et al. (2011) generated and characterized transgenic mice overexpressing Sox3. They showed that ectopic expression of Sox3 in uncommitted XX gonads was sufficient to divert the program of ovarian development toward testis formation, leading to XX males. Further analysis revealed that Sox3 induced testis differentiation in this particular line of mice by upregulating expression of Sox9 via a mechanism similar to that of Sry.
In affected members of a family with X-linked intellectual developmental disorder and isolated growth hormone deficiency (see 300123) reported by Hamel et al. (1996), Laumonnier et al. (2002) identified a 33-bp duplication (711-743dup) in the SOX3 gene. The duplication codes for 11 alanines in a polyalanine tract, predicted to cause expansion of the normal polyalanine tract (amino acids 234-249) by 15 to 26 alanine residues. The family had been described clinically by Hamel et al. (1996). Clinical examination revealed facial anomalies in some, but not all, of the patients. On average, untreated patients reached their final height, ranging from 135 to 159 cm, at the age of 24 or 25 years. In all patients examined, behavior was considered infantile, and laboratory investigations demonstrated total growth hormone deficiency.
In 2 male maternal half sibs with X-linked panhypopituitarism (312000), Woods et al. (2005) identified a submicroscopic duplication of Xq27.1 (685.6 kb) containing the SOX3 gene. Brain MRI showed anterior pituitary hypoplasia, ectopic posterior pituitary, and absent infundibulum. Mental retardation was not present.
In 4 brothers, born of a consanguineous Qatari couple, with X-linked panhypopituitarism (312000), Woods et al. (2005) identified a 21-bp duplication between nucleotides 720 and 721 of the SOX3 gene. The duplication resulted in an in-frame addition of 7 alanine residues within a polyalanine tract (Ala(7)240ins241). The sibs had absent infundibulum, severe anterior pituitary hypoplasia, and ectopic posterior pituitary. There was no associated mental retardation. The mother of all 4 children, who was heterozygous for this mutation, did not exhibit significantly skewed X inactivation in DNA extracted from blood. In vitro functional expression studies indicated that the expansion was associated with decreased SOX3 activity and impaired nuclear localization of the mutant protein.
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Rizzoti, K., Brunelli, S., Carmignac, D., Thomas, P. Q., Robinson, I. C., Lovell-Badge, R. SOX3 is required during the formation of the hypothalamo-pituitary axis. Nature Genet. 36: 247-255, 2004. [PubMed: 14981518] [Full Text: https://doi.org/10.1038/ng1309]
Solomon, N. M., Ross, S. A., Forrest, S. M., Thomas, P. Q., Morgan, T., Belsky, J. L., Hol, F. A., Karnes, P. S., Hopwood, N. J., Myers, S. E., Tan, A. S., Warne, G. L. Array comparative genomic hybridisation analysis of boys with X-linked hypopituitarism identifies a 3.9 Mb duplicated critical region at Xq27 containing SOX3. (Letter) J. Med. Genet. 44: e75, 2007. Note: Electronic Article. [PubMed: 17400794] [Full Text: https://doi.org/10.1136/jmg.2007.049049]
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Weiss, J., Meeks, J. J., Hurley, L., Raverot, G., Frassetto, A., Jameson, J. L. Sox3 is required for gonadal function, but not sex determination, in males and females. Molec. Cell. Biol. 23: 8084-8091, 2003. [PubMed: 14585968] [Full Text: https://doi.org/10.1128/MCB.23.22.8084-8091.2003]
Woods, K. S., Cundall, M., Turton, J., Rizotti, K., Mehta, A., Palmer, R., Wong, J., Chong, W. K., Al-Zyoud, M., El-Ali, M., Otonkoski, T., Martinez-Barbera, J.-P., Thomas, P. Q., Robinson, I. C., Lovell-Badge, R., Woodward, K. J., Dattani, M. T. Over- and underdosage of SOX3 is associated with infundibular hypoplasia and hypopituitarism. Am. J. Hum. Genet. 76: 833-849, 2005. [PubMed: 15800844] [Full Text: https://doi.org/10.1086/430134]
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