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Lymphoedema – pathology and clinical features
Published in Ken Myers, Paul Hannah, Marcus Cremonese, Lourens Bester, Phil Bekhor, Attilio Cavezzi, Marianne de Maeseneer, Greg Goodman, David Jenkins, Herman Lee, Adrian Lim, David Mitchell, Nick Morrison, Andrew Nicolaides, Hugo Partsch, Tony Penington, Neil Piller, Stefania Roberts, Greg Seeley, Paul Thibault, Steve Yelland, Manual of Venous and Lymphatic Diseases, 2017
Ken Myers, Paul Hannah, Marcus Cremonese, Lourens Bester, Phil Bekhor, Attilio Cavezzi, Marianne de Maeseneer, Greg Goodman, David Jenkins, Herman Lee, Adrian Lim, David Mitchell, Nick Morrison, Andrew Nicolaides, Hugo Partsch, Tony Penington, Neil Piller, Stefania Roberts, Greg Seeley, Paul Thibault, Steve Yelland
Hypotrichosis lymphoedema telangiectasia syndrome is characterized by hair loss during infancy, lymphoedema in the lower limbs developing in puberty and telangiectasia particularly on the palms and soles. It is associated with a mutation of the transcription factor gene SOX18.
Vascular tumours and malformation
Published in Brice Antao, S Irish Michael, Anthony Lander, S Rothenberg MD Steven, Succeeding in Paediatric Surgery Examinations, 2017
Cameron C Trenor III, Steven J Fishman, Arin K Greene
RASA1 mutations cause capillary malformation–arteriovenous malformation; patients have cutaneous stains and arteriovenous malformations. PTEN mutations cause lipovascular hamartomas, atypical arteriovenous malformations without capillary stains as well as frontal bossing and penile freckling. VEGFR3 mutations can result in congenital lymphoedema. Mutations in TIE2 can cause sporadic venous malformations as well as hereditary cutaneomucosal lesions. FOXC2 mutations are responsible for lymphoedema–distichiasis syndrome; patients have congenital lymphoedema and a double row of eyelashes. Glomulin mutations cause glomuvenous malformations; lesions are small, bluish and painful. Endoglin mutations result in hereditary haemorrhagic telangiectasia. Mutations in KRIT1 are responsible for cerebral cavernous malformations. SOX18 mutations cause hypotrichosis–lymphoedema–telangiectasia syndrome.
Lymphatic malformations
Published in Prem Puri, Newborn Surgery, 2017
Emily R. Christison-Lagay, Jacob C. Langer
Overexpression of the isoforms VEGF-C and VEGF-D in transgenic mice induces the formation of hyperplastic lymphatic vessels.6 Kinase-inactivating mutations in the human VEGFR3 gene result in Milroy disease.15–17 Mutations in Sox18 are associated with hypotrichosis–lymphedema–telangiectasia.9 Tie-2-deficient mouse embryos demonstrate normal initial vasculogenesis but have a disorganized vascular network lacking appropriate hierarchical organization.18 Tie-1-deficient models demonstrate decreased endothelial cell integration leading to embryonic edema, hemorrhage, and death, and the Tie-1 receptor has recently been shown to be required for normal embryonic lymphangiogenesis.19,20 Ang1–4, members of the angiopoietin family, likely have roles in vessel stabilization and lymphatic development.21 Mutations in the Fox family of transcription factors have been associated with congenital lymphedema, and this family is thought to play a role in the formation of lymphatic valves.22,23 Mutations or deletions in specific integrin subtypes can lead to abnormal lymphatic development.24 Recently, integrin-α9 was found to be necessary for normal lymphatic valve morphogenesis and may be implicated as a candidate gene for primary lymphedema caused by valve defects.25–27
Augmented angiogenic transcription factor, SOX18, is associated with asthma exacerbation
Published in Journal of Asthma, 2021
Jisu Hong, Pureun-Haneul Lee, Yun-Gi Lee, George D. Leikauf, An-Soo Jang
SOX18 is a transcription factor involved in a range of physiological processes, including differentiation of endothelial cells during new vessel formation (43–45). SOX18 is highly expressed in various types of cancer and may serve as a prognostic factor and a promising therapeutic strategy for hepatocellular carcinoma and skin cancer, and lung cancers (48–50). Previously, SOX18 has not been investigated in asthma. In this study, SOX18 expression increased in a mouse model of asthma. Although plasma SOX18 tended to be higher in subject with asthma compared to control subjects and increased more during exacerbation as compared to stable asthmatics suggesting that SOX18 is associated with asthma exacerbation related to angiogenesis and airway remodeling (50).
Functional domain analysis of SOX18 transcription factor using a single-chain variable fragment-based approach
Published in mAbs, 2018
Frank R. Fontaine, Stephen Goodall, Jeremy W. Prokop, Christopher B. Howard, Mehdi Moustaqil, Sumukh Kumble, Daniel T. Rasicci, Geoffrey W. Osborne, Yann Gambin, Emma Sierecki, Martina L. Jones, Johannes Zuegg, Stephen Mahler, Mathias Francois
Here, we report the discovery and characterization of a new biologic that proves to be useful for deciphering the molecular mode of action of a transcriptional regulator, the SOX18 transcription factor.27,28 The novel human antibody recognizes a highly conserved 8-aa motif directly positioned on the C-terminal extremity of the HMG-Box of the SOX18 protein. This antibody displays selective disruption of SOX18 self-assembly and inhibits SOX18-mediated transcriptional activation in cells. As expected, the reformatting into a complete human IgG1 antibody (Suppl. to Fig. 1, panel C) substantially improved affinity as measured by the dissociation constant (Fig. 1D, Suppl. to Fig. 3, panel B). However, the overall effect of reformatting on SOX18-blocking efficacy remains to be evaluated in vitro and in vivo. If the F5 mAb affinity level can be preserved during affinity maturation, its efficacy in blocking SOX18 homodimerization could be further improved by decreasing its concentration-independent off rate, currently estimated at 10−3 s−1 (Fig. 1D). Despite dissociation constants in the low to mid nanoMolar range, denoting strong affinity from full-length antibody or scFv for their epitope, neither were able to competitively displace the HMG-box from its DNA binding site (Fig. 3A, and Suppl. to Fig. 3, panel B). These data combined with our results obtained on protein partner recruitment using ALPHAScreen assay (Fig. 3B) strongly suggest that the mode of action of this antibody is via disruption of SOX18′s protein-protein interaction. The possibility that the epitope was located on α-Helix 1 or 2 was rapidly dismissed, as these two helixes are largely involved in protein-DNA interaction (Suppl. to Fig. 3, panel A, red crosses indicate regions involved in protein-DNA binding), which would not fit with observed non-competitive binding.24 One potential position for the F5 epitope was α-Helix 3, involved only in a limited manner in protein-DNA interaction (Suppl. to Fig. 3, panel A), and already described in literature as engaged in protein-protein interactions.42,43 However, a α-Helix 3 peptide was not recognized by the scFv F5 antibody (Suppl. to Fig. 3, panel C). This pointed towards an epitope located in the N-terminal region outside the SOX18 HMG-box or in the C-terminal region adjacent to the HMG-box, near α-Helix 3. On the 109-aa peptide, the N-terminal region adjacent to the HMG domain consists of only 9 amino acids, compared to the 28-aa C-terminal region. In addition, SOX9 homodimer is not disrupted by the scFv F5 antibody (Fig. 3B), and a SOX9 dimerization domain has been identified on the N-terminal side of SOX9 HMG.40 Taken together, this evidence prompted us to prioritize epitope mapping on the C-terminal region of SOX18-HMG.