Research ExplorerPublicationsMutations in EPHB4 cause human venous valve aplasia

Mutations in EPHB4 cause human venous valve aplasia

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Mutations in EPHB4 cause human venous valve aplasia. / Lyons, Oliver; Walker, James; Seet, Christopher; Ikram, Mohammed; Kuchta, Adam; Arnold, Andrew; Hernández-Vásquez, Magda; Frye, Maike; Vizcay-Barrena, Gema; Fleck, Roland A; Patel, Ashish S; Padayachee, Soundrie; Mortimer, Peter; Jeffery, Steve; Berland, Siren; Mansour, Sahar; Ostergaard, Pia; Makinen, Taija; Modarai, Bijan; Saha, Prakash; Smith, Alberto.

In: JCI INSIGHT, Vol. 6, No. 18, e140952, 22.09.2021.

Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review

Harvard

Lyons, O, Walker, J, Seet, C, Ikram, M, Kuchta, A, Arnold, A, Hernández-Vásquez, M, Frye, M, Vizcay-Barrena, G, Fleck, RA, Patel, AS, Padayachee, S, Mortimer, P, Jeffery, S, Berland, S, Mansour, S, Ostergaard, P, Makinen, T, Modarai, B, Saha, P & Smith, A 2021, 'Mutations in EPHB4 cause human venous valve aplasia', JCI INSIGHT, vol. 6, no. 18, e140952. https://doi.org/10.1172/jci.insight.140952

APA

Lyons, O., Walker, J., Seet, C., Ikram, M., Kuchta, A., Arnold, A., Hernández-Vásquez, M., Frye, M., Vizcay-Barrena, G., Fleck, R. A., Patel, A. S., Padayachee, S., Mortimer, P., Jeffery, S., Berland, S., Mansour, S., Ostergaard, P., Makinen, T., Modarai, B., ... Smith, A. (2021). Mutations in EPHB4 cause human venous valve aplasia. JCI INSIGHT, 6(18), [e140952]. https://doi.org/10.1172/jci.insight.140952

Vancouver

Lyons O, Walker J, Seet C, Ikram M, Kuchta A, Arnold A et al. Mutations in EPHB4 cause human venous valve aplasia. JCI INSIGHT. 2021 Sep 22;6(18). e140952. https://doi.org/10.1172/jci.insight.140952

Bibtex

@article{a8c02b968be347488fbd6cabb7755229,
title = "Mutations in EPHB4 cause human venous valve aplasia",
abstract = "Venous valve (VV) failure causes chronic venous insufficiency, but the molecular regulation of valve development is poorly understood. A primary lymphatic anomaly, caused by mutations in the receptor tyrosine kinase EPHB4, was recently described, with these patients also presenting with venous insufficiency. Whether the venous anomalies are the result of an effect on VVs is not known. VV formation requires complex {"}organization{"} of valve-forming endothelial cells, including their reorientation perpendicular to the direction of blood flow. Using quantitative ultrasound, we identified substantial VV aplasia and deep venous reflux in patients with mutations in EPHB4. We used a GFP reporter in mice to study expression of its ligand, ephrinB2, and analyzed developmental phenotypes after conditional deletion of floxed Ephb4 and Efnb2 alleles. EphB4 and ephrinB2 expression patterns were dynamically regulated around organizing valve-forming cells. Efnb2 deletion disrupted the normal endothelial expression patterns of the gap junction proteins connexin37 and connexin43 (both required for normal valve development) around reorientating valve-forming cells and produced deficient valve-forming cell elongation, reorientation, polarity, and proliferation. Ephb4 was also required for valve-forming cell organization and subsequent growth of the valve leaflets. These results uncover a potentially novel cause of primary human VV aplasia.",
keywords = "Animals, Aorta/ultrastructure, Cell Communication, Cell Polarity, Cell Proliferation, Connexin 43/metabolism, Connexins/metabolism, Endothelium, Ephrin-B2/genetics, Humans, Mice, Mice, Knockout, Mutation, Phenotype, Receptor, EphB4/genetics, Ultrasonography, Vascular Malformations/diagnostic imaging, Venous Insufficiency/diagnostic imaging, Venous Valves/abnormalities",
author = "Oliver Lyons and James Walker and Christopher Seet and Mohammed Ikram and Adam Kuchta and Andrew Arnold and Magda Hern{\'a}ndez-V{\'a}squez and Maike Frye and Gema Vizcay-Barrena and Fleck, {Roland A} and Patel, {Ashish S} and Soundrie Padayachee and Peter Mortimer and Steve Jeffery and Siren Berland and Sahar Mansour and Pia Ostergaard and Taija Makinen and Bijan Modarai and Prakash Saha and Alberto Smith",
year = "2021",
month = sep,
day = "22",
doi = "10.1172/jci.insight.140952",
language = "English",
volume = "6",
journal = "JCI INSIGHT",
issn = "2379-3708",
publisher = "The American Society for Clinical Investigation",
number = "18",

}

RIS

TY - JOUR

T1 - Mutations in EPHB4 cause human venous valve aplasia

AU - Lyons, Oliver

AU - Walker, James

AU - Seet, Christopher

AU - Ikram, Mohammed

AU - Kuchta, Adam

AU - Arnold, Andrew

AU - Hernández-Vásquez, Magda

AU - Frye, Maike

AU - Vizcay-Barrena, Gema

AU - Fleck, Roland A

AU - Patel, Ashish S

AU - Padayachee, Soundrie

AU - Mortimer, Peter

AU - Jeffery, Steve

AU - Berland, Siren

AU - Mansour, Sahar

AU - Ostergaard, Pia

AU - Makinen, Taija

AU - Modarai, Bijan

AU - Saha, Prakash

AU - Smith, Alberto

PY - 2021/9/22

Y1 - 2021/9/22

N2 - Venous valve (VV) failure causes chronic venous insufficiency, but the molecular regulation of valve development is poorly understood. A primary lymphatic anomaly, caused by mutations in the receptor tyrosine kinase EPHB4, was recently described, with these patients also presenting with venous insufficiency. Whether the venous anomalies are the result of an effect on VVs is not known. VV formation requires complex "organization" of valve-forming endothelial cells, including their reorientation perpendicular to the direction of blood flow. Using quantitative ultrasound, we identified substantial VV aplasia and deep venous reflux in patients with mutations in EPHB4. We used a GFP reporter in mice to study expression of its ligand, ephrinB2, and analyzed developmental phenotypes after conditional deletion of floxed Ephb4 and Efnb2 alleles. EphB4 and ephrinB2 expression patterns were dynamically regulated around organizing valve-forming cells. Efnb2 deletion disrupted the normal endothelial expression patterns of the gap junction proteins connexin37 and connexin43 (both required for normal valve development) around reorientating valve-forming cells and produced deficient valve-forming cell elongation, reorientation, polarity, and proliferation. Ephb4 was also required for valve-forming cell organization and subsequent growth of the valve leaflets. These results uncover a potentially novel cause of primary human VV aplasia.

AB - Venous valve (VV) failure causes chronic venous insufficiency, but the molecular regulation of valve development is poorly understood. A primary lymphatic anomaly, caused by mutations in the receptor tyrosine kinase EPHB4, was recently described, with these patients also presenting with venous insufficiency. Whether the venous anomalies are the result of an effect on VVs is not known. VV formation requires complex "organization" of valve-forming endothelial cells, including their reorientation perpendicular to the direction of blood flow. Using quantitative ultrasound, we identified substantial VV aplasia and deep venous reflux in patients with mutations in EPHB4. We used a GFP reporter in mice to study expression of its ligand, ephrinB2, and analyzed developmental phenotypes after conditional deletion of floxed Ephb4 and Efnb2 alleles. EphB4 and ephrinB2 expression patterns were dynamically regulated around organizing valve-forming cells. Efnb2 deletion disrupted the normal endothelial expression patterns of the gap junction proteins connexin37 and connexin43 (both required for normal valve development) around reorientating valve-forming cells and produced deficient valve-forming cell elongation, reorientation, polarity, and proliferation. Ephb4 was also required for valve-forming cell organization and subsequent growth of the valve leaflets. These results uncover a potentially novel cause of primary human VV aplasia.

KW - Animals

KW - Aorta/ultrastructure

KW - Cell Communication

KW - Cell Polarity

KW - Cell Proliferation

KW - Connexin 43/metabolism

KW - Connexins/metabolism

KW - Endothelium

KW - Ephrin-B2/genetics

KW - Humans

KW - Mice

KW - Mice, Knockout

KW - Mutation

KW - Phenotype

KW - Receptor, EphB4/genetics

KW - Ultrasonography

KW - Vascular Malformations/diagnostic imaging

KW - Venous Insufficiency/diagnostic imaging

KW - Venous Valves/abnormalities

U2 - 10.1172/jci.insight.140952

DO - 10.1172/jci.insight.140952

M3 - SCORING: Journal article

C2 - 34403370

VL - 6

JO - JCI INSIGHT

JF - JCI INSIGHT

SN - 2379-3708

IS - 18

M1 - e140952

ER -