HGNC Approved Gene Symbol: SOX18
SNOMEDCT: 723363009;
Cytogenetic location: 20q13.33 Genomic coordinates (GRCh38): 20:64,047,582-64,049,639 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 20q13.33 | Hypotrichosis-lymphedema-telangiectasia syndrome | 607823 | Autosomal recessive | 3 |
| Hypotrichosis-lymphedema-telangiectasia-renal defect syndrome | 137940 | Autosomal dominant | 3 |
The testis-determining gene SRY (480000) encodes a transcription factor characterized by a DNA-binding motif known as the HMG (high mobility group) domain. The SOX gene family consists of genes related to SRY, with a sequence identity of more than 60% to the SRY HMG box. See 600898.
Greenfield et al. (1996) described a novel member of the mouse Sox gene family, Sox18, which is transcribed in adult lung and in cardiac and skeletal muscle. They reported that the Sox18 protein binds the sequence AACAAAG in vitro and that it is capable of transactivating gene expression. Pennisi et al. (2000) found that Sox18 is expressed in the developing vascular endothelium and hair follicles in mouse embryos.
By EST database searching for sequences with an HMG-box, followed by 3-prime and 5-prime RACE, Azuma et al. (2000) identified a partial cDNA sequence which they then used to screen a human heart cDNA library. They isolated a cDNA clone encoding a deduced 384-amino acid protein that shares 83% identity with the mouse Sox18 protein. Northern blot analysis showed that a 1.9-kb SOX18 transcript is predominantly expressed in the heart, although weak signals are seen in brain, liver, testis, and leukocytes.
On the basis of linkage analysis, Greenfield et al. (1996) mapped the Sox18 gene to distal mouse chromosome 2. They noted that distal mouse chromosome 2 includes 1 of 10 known imprinted regions in the mouse. By homology, the human SOX18 gene would map to chromosome 20q. By PCR-based analyses with both a human/rodent monochromosomal hybrid cell panel and a radiation hybrid panel, Azuma et al. (2000) mapped the SOX18 gene to 20q13.33. Pennisi et al. (2000) also confirmed the assignment of the SOX18 gene to 20q13.3 by radiation hybrid analysis.
Hypotrichosis-Lymphedema-Telangiectasia Syndrome
Using microsatellite analysis in 3 families with hypotrichosis-lymphedema-telangiectasia syndrome (HLTS; 607823), Irrthum et al. (2003) excluded the VEGFR3 (136352) and FOXC2 (602402) genes, which are related to other disorders involving lymphedema, as candidate genes. They identified the murine 'ragged' phenotype, which is caused by mutation in the Sox18 gene, as a likely counterpart of HLTS because it presents a combination of hair and cardiovascular anomalies, including symptoms of lymphatic dysfunction. In affected members of 2 consanguineous families, they identified homozygous missense mutations (A104P, 601618.0001 and W95R, 601618.0002), both of which affected the DNA-binding domain. Functional studies of the variants were not performed.
In a 13-year-old girl with hypotrichosis, telangiectasia, and dilation of the ascending aorta, who did not exhibit lymphedema, Wunnemann et al. (2016) performed whole-exome sequencing and identified heterozygosity for a de novo nonsense mutation in the SOX18 gene (Q161X; 601618.0004).
Hypotrichosis-Lymphedema-Telangiectasia-Renal Defect Syndrome
In a boy originally diagnosed with HLTS, Irrthum et al. (2003) identified a heterozygous nonsense mutation (C240X; 601618.0003) in the SOX18 gene. His affected brother, who died in utero with hydrops fetalis, also carried the mutation. The mutation, which truncated the SOX18 protein in its transactivation domain, was not found in genomic DNA from either parent and was thought to constitute a de novo germline mutation. Moalem et al. (2015) reported that the surviving brother reported by Irrthum et al. (2003) had developed renal failure, and proposed that the diagnosis be revised to HLTS with renal defect (HLTRS; 137940). Functional studies were not performed, but Moalem et al. (2015) postulated a dominant-negative effect.
In the patient with HLTRS reported by Proesmans et al. (1989), Moalem et al. (2015) identified a de novo heterozygous C240X mutation in the SOX18 gene.
Greenfield et al. (1996) noted that Sox18 is a candidate for 2 mouse mutants, 'ragged' and 'wasting.' 'Ragged' heterozygous mice are viable and healthy with thin ragged coats composed of guard hairs and awls. Homozygotes almost completely lack vibrissae and coat hairs, display generalized edema and cyanosis, rarely survive past weaning, and, depending on the genetic background, may have an accumulation of chyle in the peritoneum. Ragged(J) mice have a phenotype indistinguishable from that of ragged mice. The ragged mutation is semidominant. Pennisi et al. (2000) identified mutations in the Sox18 gene that underlie the cardiovascular and hair follicle defects in ragged mice. The ragged phenotype is caused by deletion of a cytosine at nucleotide 960 of the murine Sox18 gene; ragged(J) is caused by deletion of a guanine at nucleotide 959. Fusion proteins containing these mutations lacked the ability to activate transcription relative to wildtype controls in an in vitro assay.
Francois et al. (2008) used molecular, cellular, and genetic assays in mice to show that Sox18 acts as a molecular switch to induce differentiation of lymphatic endothelial cells. Sox18 is expressed in a subset of cardinal vein cells that later coexpress Prox1 (610546) and migrate to form lymphatic vessels. Sox18 directly activates Prox1 transcription by binding to its proximal promoter. Overexpression of Sox18 in blood vascular endothelial cells induced them to express Prox1 and other lymphatic endothelial markers, while Sox18-null embryos showed a complete blockade of lymphatic endothelial cell differentiation from the cardinal vein. Francois et al. (2008) concluded that their findings demonstrated a critical role for Sox18 in developmental lymphangiogenesis, and suggested new avenues to investigate for therapeutic management of human lymphangiopathies.
In embryos of the naturally occurring Sox18-mutant mouse strain ragged-opossum (RaOp), Downes et al. (2009) demonstrated that early genesis and patterning of vasculature was unimpaired, but surface capillaries became enlarged from 12.5 days postcoitum, and that embryos developed massive surface hemorrhage by 14.5 days postcoitum. Large focal breaches in the endothelial barrier were observed, in addition to endothelial hyperplasia associated with impaired pericyte recruitment to the microvasculature. Expression of the genes encoding the endothelial factors MMP7 (178990), IL7R (146661), and N-cadherin (CDH2; 114020) was reduced in RaOp embryos, suggesting that these may be downstream targets of SOX18. Downes et al. (2009) hypothesized that vascular anomalies in HLTS arise from defects in regulation of genes required for the acquisition of structural integrity during microvascular maturation.
In a family reported by Devriendt et al. (2002) in which a male and female child of first-cousin Belgian parents were affected with hypotrichosis-lymphedema-telangiectasia syndrome (HLTS; 607823), Irrthum et al. (2003) identified homozygosity for a 455G-C transversion in the SOX18 gene, resulting in an ala104-to-pro (A104P) substitution. The mutation was present in heterozygous state in the unaffected parents.
In a 12-year-old Turkish girl with hypotrichosis-lymphedema-telangiectasia syndrome (HLTS; 607823) described by Glade et al. (2001), Irrthum et al. (2003) identified a homozygous 428T-A transversion in the SOX18 gene, resulting in a trp95-to-arg (W95R) substitution. Her parents were first cousins.
In a boy with hypotrichosis-lymphedema-telangiectasia-renal defect syndrome (HLTRS; 137940) and in tissue from his brother, who died in utero at 30 weeks' gestation, Irrthum et al. (2003) identified a heterozygous 865C-A transversion in the SOX18 gene, resulting in a cys240-to-ter (C240X) substitution. The mutation, which truncated the SOX18 protein in its transactivation domain, was not found in genomic DNA from either parent and was thought to constitute a de novo germline mutation. The brothers were originally reported by Irrthum et al. (2003) to have HLTS (607823); however, Moalem et al. (2015) reported that the surviving brother had developed renal failure, and proposed that the diagnosis be revised to HLTS with renal defect (HLTRS). Functional studies were not performed, but Moalem et al. (2015) postulated a dominant-negative effect.
In the patient with HLTRS reported by Proesmans et al. (1989), Moalem et al. (2015) identified a de novo heterozygous C240X mutation in the SOX18 gene.
In a 13-year-old girl with hypotrichosis and telangiectasia (HTLS; 607823), who also exhibited severe dilation of the ascending aorta, Wunnemann et al. (2016) identified heterozygosity for a de novo c.481C-T transition (c.481C-T, NM_018419.2) in the SOX18 gene, resulting in a gln161-to-ter (Q161X) substitution. The mutation was not found in her unaffected parents or brother, in an in-house database of 360 exomes from French Canadian controls, or in the ExAC database.
Azuma, T., Seki, N., Yoshikawa, T., Saito, T., Masuho, Y., Muramatsu, M. cDNA cloning, tissue expression, and chromosome mapping of human homolog of SOX18. J. Hum. Genet. 45: 192-195, 2000. [PubMed: 10807548] [Full Text: https://doi.org/10.1007/s100380050210]
Devriendt, K., Vikkula, M., Irrthum, A., Mattjijs, G., Mertens, A., Fryns, J.-P. Autosomal recessive alopecia and lymphedema. (Abstract) Genet. Counsel. 13: 74-75, 2002.
Downes, M., Francois, M., Ferguson, C., Parton, R. G., Koopman, P. Vascular defects in the mouse model of hypotrichosis-lymphedema-telangiectasia syndrome indicate a role for SOX18 in blood vessel maturation. Hum. Molec. Genet. 18: 2839-2850, 2009. [PubMed: 19429912] [Full Text: https://doi.org/10.1093/hmg/ddp219]
Francois, M., Caprini, A., Hosking, B., Orsenigo, F., Wilhelm, D., Browne, C., Paavonen, K., Karnezis, T., Shayan, R., Downes, M., Davidson, T., Tutt, D., Cheah, K. S. E., Stacker, S. A., Muscat, G. E. O., Achen, M. G., Dejana, E., Koopman, P. Sox18 induces development of the lymphatic vasculature in mice. Nature 456: 643-647, 2008. [PubMed: 18931657] [Full Text: https://doi.org/10.1038/nature07391]
Glade, C., van Steensel, M. A., Steijlen, P. M. Hypotrichosis, lymphedema of the legs and acral telangiectasias--new syndrome? Europ. J. Derm. 11: 515-517, 2001. [PubMed: 11701398]
Greenfield, A., Dunn, T., Muscat, G., Koopman, P. The Sry-related gene Sox18 maps to distal mouse chromosome 2. Genomics 36: 558-559, 1996. [PubMed: 8884288] [Full Text: https://doi.org/10.1006/geno.1996.0510]
Irrthum, A., Devriendt, K., Chitayat, D., Matthijs, G., Glade, C., Steijlen, P. M., Fryns, J.-P., Van Steensel, A. M., Vikkula, M. Mutations in the transcription factor gene SOX18 underlie recessive and dominant forms of hypotrichosis-lymphedema-telangiectasia. Am. J. Hum. Genet. 72: 1470-1478, 2003. [PubMed: 12740761] [Full Text: https://doi.org/10.1086/375614]
Moalem, S., Brouillard, P., Kuypers, D., Legius, E., Harvey, E., Taylor, G., Francois, M., Vikkula, M., Chitayat, D. Hypotrichosis-lymphedema -telangiectasia-renal defect associated with a truncating mutation in the SOX18 gene. Clin. Genet. 87: 378-382, 2015. [PubMed: 24697860] [Full Text: https://doi.org/10.1111/cge.12388]
Pennisi, D., Gardner, J., Chambers, D., Hosking, B., Peters, J., Muscat, G., Abbott, C., Koopman, P. Mutations in Sox18 underlie cardiovascular and hair follicle defects in ragged mice. Nature Genet. 24: 434-437, 2000. [PubMed: 10742113] [Full Text: https://doi.org/10.1038/74301]
Pennisi, D. J., James, K. M., Hosking, B., Muscat, G. E. O., Koopman, P. Structure, mapping, and expression of human SOX18. Mammalian Genome 11: 1147-1149, 2000. [PubMed: 11130989] [Full Text: https://doi.org/10.1007/s003350010216]
Proesmans, W., Legius, E., Van Herck, K., Van Damme, B. Cutaneous telangiectasia, sparse hair and membranoproliferative glomerulonephritis: a new case of a newly recognized entity. Pediat. Nephrol. 3: 162-165, 1989. [PubMed: 2484451] [Full Text: https://doi.org/10.1007/BF00852899]
Wunnemann, F., Kokta, V., Leclerc, S., Thibeault, M., McCuaig, C., Hatami, A., Stheneur, C., Grenier, J.-C., Awadalla, P., Mitchell, G. A., Andelfinger, G., Preuss, C. Aortic dilatation associated with a de novo mutation in the SOX18 gene: expanding the clinical spectrum of hypotrichosis-lymphedema-telangiectasia syndrome. Canad. J. Cardiol. 32: 135.e1-135.e7, 2016. Note: Electronic Article. [PubMed: 26148450] [Full Text: https://doi.org/10.1016/j.cjca.2015.04.004]