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One our other pages involving genetically caused lymphedema, we read about the VEGF gene and the FOXC2 gene.

Another gene that has been identified is the SOX18 gene. This mutations of this gene are responsible for hypotrichosis-lymphedema-telangiectasia syndrome.

The “SOX” family

SOX1, SOX2, SOX3, SOX4, SOX5, SOX6, SOX7, SOX8, SOX9, SOX10, SOX11, SOX12, SOX13, SOX14, SOX15, SOX17, SOX18, SOX21, SOX30

The SOX family plays a critical role in the formation of tissues and organs during embryonic development. The SOX gene family also maintains the normal function of certain cells after birth. To carry out these roles, proteins made by genes in the SOX family bind to specific areas of DNA. By attaching to critical regions near genes, SOX proteins help control the activity of those genes. SOX proteins are called transcription factors on the basis of this action.



Gene map locus 20q13.33 TEXT


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.


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. By sequencing the SOX18 gene in the 3 HLTS families, they identified homozygous missense mutations (601618.0001 and 601618.0002) in affected members of 2 consanguineous families and a heterozygous nonsense mutation (601618.0003) in an affected child and his brother, who died in utero with hydrops fetalis, of a nonconsanguineous family. The nonsense 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.


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 comprised 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.


(selected examples)


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 (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 (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 syndrome (607823) and in tissue from his deceased 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 was not present in the genomic DNA of the unaffected nonconsanguineous parents.

Online Mendalian Inheritance in Man

Cloning and functional analysis of the Sry-related HMG box gene, Sox18

Hosking BM, Wyeth JR, Pennisi DJ, Wang SC, Koopman P, Muscat GE.

University of Queensland, Institute for Molecular Bioscience, Centre for Molecular and Cellular Biology, Ritchie Research Laboratories, B402A, St Lucia, 4072, Queensland, Australia.

The Sox gene family (Sry like HMG box gene) is characterised by a conserved DNA sequence encoding a domain of approximately 80 amino acids which is responsible for sequence specific DNA binding. We initially published the identification and partial cDNA sequence of murine Sox18, a new member of this gene family, isolated from a cardiac cDNA library. This sequence allowed us to classify Sox18 into the F sub-group of Sox proteins, along with Sox7 and Sox17. Recently, we demonstrated that mutations in the Sox18 activation domain underlie cardiovascular and hair follicle defects in the mouse mutation, ragged (Ra) (Pennisi et al., 2000. Mutations in Sox18 underlie cardiovascular and hair follicle defecs in ragged mice. Nat. Genet. 24, 434-437). Ra homozygotes lack vibrissae and coat hairs, have generalised oedema and an accumulation of chyle in the peritoneum. Here we have investigated the genomic sequences encoding Sox18. Screening of a mouse genomic phage library identified four overlapping clones, we sequenced a 3.25 kb XbaI fragment that defined the entire coding region and approximately 1.5 kb of 5' flanking sequences. This identified (i) an additional 91 amino acids upstream of the previously designated methionine start codon in the original cDNA, and (ii) an intron encoded within the HMG box/DNA binding domain in exactly the same position as that found in the Sox5, -13 and -17 genes. The Sox18 gene encodes a protein of 468 aa. We present evidence that suggests HAF-2, the human HMG-box activating factor -2 protein, is the orthologue of murine Sox18. HAF-2 has been implicated in the regulation of the Human IgH enhancer in a B cell context. Random mutagenesis coupled with GAL4 hybrid analysis in the activation domain between amino acids 252 and 346, of Sox18, implicated the phosphorylation motif, SARS, and the region between amino acid residues 313 and 346 as critical components of Sox18 mediated transactivation. Finally, we examined the expression of Sox18 in multiple adult mouse tissues using RT-PCR. Low-moderate expression was observed in spleen, stomach, kidney, intestine, skeletal muscle and heart. Very abundant expression was detected in lung tissue.

PMID: 11179689 [PubMed - indexed for MEDLINE]

The human SOX18 gene: cDNA cloning and high resolution mapping.

Stanojcic S, Stevanovic M.

Institute of Molecular Genetics and Genetic Engineering, Vojvode Stepe 444a, PO Box 794, 11001 Belgrade, Yugoslavia.

SOX genes comprise a family of genes that are related to the mammalian sex determining gene SRY and these genes play key roles during animal development. We report here cloning and characterisation of the human SOX18 gene. SOX18 gene is expressed in foetal brain as well as in a wide range of foetal and adult tissues indicating its function is not restricted to early development. Mapping analysis has revealed that SOX18 gene is located on human chromosome 20q13.3, 27.29 cR distal from the marker D20S173.

PMID: 10858556 [PubMed - indexed for MEDLINE]


SOX genes: architects of development

Prior HM, Walter MA.

Ocular Genetics Research Group, University of Alberta, Edmonton, Canada.

Development in higher organisms involves complex genetic regulation at the molecular level. The emerging picture of development control includes several families of master regulatory genes which can affect the expression of down-stream target genes in developmental cascade pathways. One new family of such development regulators is the SOX gene family. The SOX genes are named for a shared motif called the SRY box a region homologous to the DNA-binding domain of SRY, the mammalian sex determining gene. Like SRY, SOX genes play important roles in chordate development. At least a dozen human SOX genes have been identified and partially characterized (Tables 1 and 2). Mutations in SOX9 have recently been linked to campomelic dysplasia and autosomal sex reversal, and other SOX genes may also be associated with human disease.

Publication Types: Review


Strangling tumours in bid to halt cancer

Tuesday 23 August 2005

It may be possible to halt cancer in its tracks by blocking a gene critical to building tumour supply lines, according to new research carried out at the University of Queensland.

Most tumours need a blood supply to grow.

Researchers at the Institute for Molecular Bioscience have found that when new blood vessels form – in developing embryos and in tumours – a gene, known as Sox18, switches on for just 48 hours.

“In adult mice, we have found that interfering with this gene reduces tumour growth by up to 80 percent,” says postdoctoral scientist Dr Neville Young. “A surprisingly large number of people carry microscopic tumours inside their bodies but these cells never develop into disease.

“One of the reasons these cancerous cells do not rage out of control is that they never establish a blood supply to feed them. Those unlucky enough to develop malignant tumours often do so when cancerous cells co-opt the body’s own blood supply.”

Sox18 has an important role to play in helping specialised cells travel to the right position and then form the tubes needed for blood flow.

Dr Young says that targeting blood vessels was not a new concept in the fight against cancer, but that one of the big problems was the side effects of current treatments.

“The novel thing about targeting Sox18 is that it is only turned on in new blood vessels feeding the growing tumour,” he says. “It does not seem to affect any other blood vessels in the body. By attacking only Sox18 we might be able to stop these new vessels forming while leaving the rest of the blood supply alone.” The next step is to test whether researchers can manufacture a drug for humans that can mimic the observed effects in mice. They also need to design a delivery system to get the drug to the growing blood vessel cells to switch Sox18 off.

The early stages of this research are already underway with preliminary results expected within two years. This is dependent on ongoing funding for this research.

Neville is one of 13 Fresh Scientists who are presenting their research to the public for the first time thanks to Fresh Science, a national program sponsored by the Federal and Victorian Governments. One of the Fresh Scientists will win a trip to the UK courtesy of the British Council to present his or her work to the Royal Institution.

Fresh Science

Redundant roles of Sox17 and Sox18 in early cardiovascular development of mouse embryos.

Biochem Biophys Res Commun. 2007 Aug

Sakamoto Y, Hara K, Kanai-Azuma M, Matsui T, Miura Y, Tsunekawa N, Kurohmaru M, Saijoh Y, Koopman P, Kanai Y. Department of Veterinary Anatomy, The University of Tokyo, Yayoi 1-1-1, Bunkyo-ku, Tokyo 113-8657, Japan.

Sox7, -17 and -18 constitute the Sox subgroup F (SoxF) of HMG box transcription factor genes, which all are co-expressed in developing vascular endothelial cells in mice. Here we characterized cardiovascular phenotypes of Sox17/Sox18-double and Sox17-single null embryos during early-somite stages. Whole-mount PECAM staining demonstrated the aberrant heart looping, enlarged cardinal vein and mild defects in anterior dorsal aorta formation in Sox17 single-null embryos. The Sox17/Sox18 double-null embryos showed more severe defects in formation of anterior dorsal aorta and head/cervical microvasculature, and in some cases, aberrant differentiation of endocardial cells and defective fusion of the endocardial tube. However, the posterior dorsal aorta and allantoic microvasculature was properly formed in all of the Sox17/Sox18 double-null embryos. The anomalies in both anterior dorsal aorta and head/cervical vasculature corresponded with the weak Sox7 expression sites. This suggests the region-specific redundant activities of three SoxF members along the anteroposterior axis of embryonic vascular network. . Science Direct

Redundant roles of Sox17 and Sox18 in postnatal angiogenesis in mice

J Cell Sci. 2006 Sep

Matsui T, Kanai-Azuma M, Hara K, Matoba S, Hiramatsu R, Kawakami H, Kurohmaru M, Koopman P, Kanai Y. Department of Veterinary Anatomy, The University of Tokyo, Yayoi 1-1-1, Bunkyo-ku, Tokyo 113-8657, Japan. Sox7, Sox17 and Sox18 constitute group F of the Sox family of HMG box transcription factor genes. Dominant-negative mutations in Sox18 underlie the cardiovascular defects observed in ragged mutant mice. By contrast, Sox18(-/-) mice are viable and fertile, and display no appreciable anomaly in their vasculature, suggesting functional compensation by the two other SoxF genes. Here, we provide direct evidence for redundant function of Sox17 and Sox18 in postnatal neovascularization by generating Sox17(+/-) -Sox18(-/-) double mutant mice. Whereas Sox18(-/-) and Sox17(+/-) -Sox18(+/-) mice showed no vascular defects, approximately half of the Sox17(+/-) -Sox18(-/-) pups died before postnatal day 21 (P21). They showed reduced neovascularization in the liver sinusoids and kidney outer medulla vasa recta at P7, which most likely caused the ischemic necrosis observed by P14 in hepatocytes and renal tubular epithelia. Those that survived to adulthood showed similar, but milder, vascular anomalies in both liver and kidney, and females were infertile with varying degrees of vascular abnormalities in the reproductive organs. These anomalies corresponded with sites of expression of Sox7 and Sox17 in the developing postnatal vasculature. In vitro angiogenesis assays, using primary endothelial cells isolated from the P7 livers, showed that the Sox17(+/-) -Sox18(-/-) endothelial cells were defective in endothelial sprouting and remodeling of the vasculature in a phenotype-dependent manner. Therefore, our findings indicate that Sox17 and Sox18, and possibly all three SoxF genes, are cooperatively involved in mammalian vascular development.

Journal of Cell Science

External Links

SOX 18 Human

SOX18 directly interacts with MEF2C in endothelial cells

Sox18 is transiently expressed during angiogenesis in granulation tissue of skin wounds with an identical expression pattern to Flk-1 mRNA

SOX18 and the transcriptional regulation of blood vessel development

Mutations in Sox18 underlie cardiovascular and hair follicle defects in ragged mice.

Lymphedema Family Study - Genetics

This is perhaps one of the most important centers for us as lymphedema patients. The pace of genetic research is exploding and it will be through this type of research that we will come to know and understand:

1.) What causes lymphedema - the genetics involved.

2.) The path to a genetic cure

3,) The ability to provide treatment.

How many times have we said, “we wished someone could find out what causes lymphedema?” Countless, countless times.

The serious problem we face now is that due to the economy funding programs for this research has almost dried up and the program in very much in danger of being shutdown early next year.

Friends, we absolutely must save this program. Should it be closed, we would loose just about our only hope of a cure. We would also loose some of the most committed doctors, and support staff.

Please visit the site and go through their information. Support them as much as it is possible.

Pat O'Connor

University of Pittsburg

Lymphedema People Related Internal Links

Lymphedema People Resources

Lymphedema Family Study

Please support this important work

Welcome to the Lymphedema Family Study at the University of Pittsburgh! The goal of this project is to identify genes responsible for primary lymphedema. It is our hope that a new understanding of the genetic basis of inherited lymphedema will provide insight into its treatment and contribute to early identification of individuals at risk. Click on the links to the left for frequently asked questions about this condition, information about the inheritance of primary lymphedema, previous investigations into the genetic aspects of lymphedema, an update of our research, and listings of our references and other lymphedema websites.

This study does not involve diagnosis or treatment of lymphedema, and it was not designed to provide any direct benefit to the participants. However, it is our hope that it will benefit many lymphedema patients in the future. If there are at least two people (including you) in your family with primary lymphedema, and you would like more information on how to become involved in the Lymphedema Family Study, please contact the coordinator of this study, Kelly Knickelbein, M.S., at the address or phone number below: Lymphedema Family Study University of Pittsburgh Department of Human Genetics A300 Crabtree Hall, GSPH Pittsburgh, PA 15261 Phone: (412) 624-4657 or (800) 263-2152 e-mail:

Please be sure to include the words LYMPHEDEMA or GENETIC in your subject line.

The Lymphatic Research Foundation

The Lymphatic Research Foundation is a 501©(3) not-for profit organization whose mission is to advance research of the lymphatic system and to find the cause of and cure for lymphatic diseases, lymphedema, and related disorders.

Updated Nov. 3, 2011

lymphedema_gene_sox18.txt · Last modified: 2012/10/16 14:40 (external edit)