Mutations in FOXC2 in Humans (Lymphoedema Distichiasis Syndrome) Cause Lymphatic Dysfunction on Dependency
Identifieur interne : 005438 ( Main/Exploration ); précédent : 005437; suivant : 005439Mutations in FOXC2 in Humans (Lymphoedema Distichiasis Syndrome) Cause Lymphatic Dysfunction on Dependency
Auteurs : Russell H. Mellor [Royaume-Uni] ; Naomi Tate [Royaume-Uni] ; Anthony W. B. Stanton [Royaume-Uni] ; Charlotte Hubert [Royaume-Uni] ; Taija M Kinen [Royaume-Uni] ; Alberto Smith [Royaume-Uni] ; Kevin G. Burnand [Royaume-Uni] ; Steve Jeffery [Royaume-Uni] ; J. Rodney Levick [Royaume-Uni] ; Peter S. Mortimer [Royaume-Uni]Source :
- Journal of vascular research [ 1018-1172 ] ; 2011.
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Abstract
Background: Human lymphoedema distichiasis syndrome (LDS) results from germline mutations in transcription factor FOXC2. In a mouse model, lack of lymphatic and venous valves is observed plus abnormal smooth muscle cell recruitment to initial lymphatics. We investigated the mechanism of lymphoedema in humans with FOXC2 mutations, specifically the effect of gravitational forces on dermal lymphatic function. Methods: We performed (1) quantitative fluorescence microlymphangiography (FML) on the skin of the forearm (non-swollen region) at heart level, and thefoot (swollen region) below heart level (dependent) and then at heart level, and (2) immunohistochemical staining of microlymphatics in forearm and foot skin biopsies, using antibodies to podoplanin, LYVE-1 and smooth muscle actin. Results: FML revealed a marked reduction in fluid uptake by initial lymphatics in the LDS foot during dependency, yet normal uptake (similar to controls) in the same foot at heart level and in LDS forearms. In control subjects, dependency did not impair initial lymphatic filling. Immunohistochemical micro-lymphatic density in forearm and foot did not differ between LDS and controls. Conclusions: FOXC2 mutations cause a functional failure of dermal initial lymphatics during gravitational stress (dependency), but not hypoplasia. The results reveal a pathophysiological mechanism contributing to swelling in LDS.
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Mellor</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Cardiac and Vascular Sciences (Dermatology), St. George's, University of London</s1><s3>GBR</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Royaume-Uni</country><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName><orgName type="university">Université de Londres</orgName></affiliation></author><author><name sortKey="Tate, Naomi" sort="Tate, Naomi" uniqKey="Tate N" first="Naomi" last="Tate">Naomi Tate</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Cardiac and Vascular Sciences (Dermatology), St. George's, University of London</s1><s3>GBR</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Royaume-Uni</country><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName><orgName type="university">Université de Londres</orgName></affiliation></author><author><name sortKey="Stanton, Anthony W B" sort="Stanton, Anthony W B" uniqKey="Stanton A" first="Anthony W. B." last="Stanton">Anthony W. B. Stanton</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Cardiac and Vascular Sciences (Dermatology), St. George's, University of London</s1><s3>GBR</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Royaume-Uni</country><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName><orgName type="university">Université de Londres</orgName></affiliation></author><author><name sortKey="Hubert, Charlotte" sort="Hubert, Charlotte" uniqKey="Hubert C" first="Charlotte" last="Hubert">Charlotte Hubert</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Cardiac and Vascular Sciences (Dermatology), St. George's, University of London</s1><s3>GBR</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Royaume-Uni</country><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName><orgName type="university">Université de Londres</orgName></affiliation></author><author><name sortKey="M Kinen, Taija" sort="M Kinen, Taija" uniqKey="M Kinen T" first="Taija" last="M Kinen">Taija M Kinen</name><affiliation wicri:level="1"><inist:fA14 i1="04"><s1>Lymphatic Development Laboratory, Cancer Research UK London Research Institute</s1><s3>GBR</s3><sZ>5 aut.</sZ></inist:fA14><country>Royaume-Uni</country><wicri:noRegion>Lymphatic Development Laboratory, Cancer Research UK London Research Institute</wicri:noRegion></affiliation></author><author><name sortKey="Smith, Alberto" sort="Smith, Alberto" uniqKey="Smith A" first="Alberto" last="Smith">Alberto Smith</name><affiliation wicri:level="3"><inist:fA14 i1="05"><s1>Academic Surgery, St. Thomas' Hospital</s1><s2>London</s2><s3>GBR</s3><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>Royaume-Uni</country><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="Burnand, Kevin G" sort="Burnand, Kevin G" uniqKey="Burnand K" first="Kevin G." last="Burnand">Kevin G. Burnand</name><affiliation wicri:level="3"><inist:fA14 i1="05"><s1>Academic Surgery, St. Thomas' Hospital</s1><s2>London</s2><s3>GBR</s3><sZ>6 aut.</sZ><sZ>7 aut.</sZ></inist:fA14><country>Royaume-Uni</country><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName></affiliation></author><author><name sortKey="Jeffery, Steve" sort="Jeffery, Steve" uniqKey="Jeffery S" first="Steve" last="Jeffery">Steve Jeffery</name><affiliation wicri:level="4"><inist:fA14 i1="02"><s1>Clinical Developmental Sciences (Medical Genetics), St. George's, University of London</s1><s3>GBR</s3><sZ>8 aut.</sZ></inist:fA14><country>Royaume-Uni</country><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName><orgName type="university">Université de Londres</orgName></affiliation></author><author><name sortKey="Levick, J Rodney" sort="Levick, J Rodney" uniqKey="Levick J" first="J. Rodney" last="Levick">J. Rodney Levick</name><affiliation wicri:level="4"><inist:fA14 i1="03"><s1>Basic Medical Sciences (Physiology), St. George's, University of London</s1><s3>GBR</s3><sZ>9 aut.</sZ></inist:fA14><country>Royaume-Uni</country><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName><orgName type="university">Université de Londres</orgName></affiliation></author><author><name sortKey="Mortimer, Peter S" sort="Mortimer, Peter S" uniqKey="Mortimer P" first="Peter S." last="Mortimer">Peter S. Mortimer</name><affiliation wicri:level="4"><inist:fA14 i1="01"><s1>Cardiac and Vascular Sciences (Dermatology), St. George's, University of London</s1><s3>GBR</s3><sZ>1 aut.</sZ><sZ>2 aut.</sZ><sZ>3 aut.</sZ><sZ>4 aut.</sZ><sZ>10 aut.</sZ></inist:fA14><country>Royaume-Uni</country><placeName><settlement type="city">Londres</settlement><region type="country">Angleterre</region><region type="région" nuts="1">Grand Londres</region></placeName><orgName type="university">Université de Londres</orgName></affiliation></author></analytic><series><title level="j" type="main">Journal of vascular research</title><title level="j" type="abbreviated">J. vasc. res.</title><idno type="ISSN">1018-1172</idno><imprint><date when="2011">2011</date></imprint></series></biblStruct></sourceDesc><seriesStmt><title level="j" type="main">Journal of vascular research</title><title level="j" type="abbreviated">J. vasc. res.</title><idno type="ISSN">1018-1172</idno></seriesStmt></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Circulatory system</term><term>Distichiasis</term><term>Dysfunction</term><term>Fluorescence</term><term>Human</term><term>Lymphatic</term><term>Lymphedema</term><term>Mammalia</term><term>Microlymphography</term><term>Mutation</term><term>Skin</term></keywords><keywords scheme="Pascal" xml:lang="fr"><term>Mutation</term><term>Lymphatique</term><term>Trouble fonctionnel</term><term>Fluorescence</term><term>Microlymphographie</term><term>Peau</term><term>Appareil circulatoire</term><term>Mammalia</term><term>Lymphoedème</term><term>Distichiasis</term><term>Homme</term></keywords><keywords scheme="Wicri" type="topic" xml:lang="fr"><term>Homme</term></keywords></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Background: Human lymphoedema distichiasis syndrome (LDS) results from germline mutations in transcription factor FOXC2. In a mouse model, lack of lymphatic and venous valves is observed plus abnormal smooth muscle cell recruitment to initial lymphatics. We investigated the mechanism of lymphoedema in humans with FOXC2 mutations, specifically the effect of gravitational forces on dermal lymphatic function. Methods: We performed (1) quantitative fluorescence microlymphangiography (FML) on the skin of the forearm (non-swollen region) at heart level, and thefoot (swollen region) below heart level (dependent) and then at heart level, and (2) immunohistochemical staining of microlymphatics in forearm and foot skin biopsies, using antibodies to podoplanin, LYVE-1 and smooth muscle actin. Results: FML revealed a marked reduction in fluid uptake by initial lymphatics in the LDS foot during dependency, yet normal uptake (similar to controls) in the same foot at heart level and in LDS forearms. In control subjects, dependency did not impair initial lymphatic filling. Immunohistochemical micro-lymphatic density in forearm and foot did not differ between LDS and controls. Conclusions: FOXC2 mutations cause a functional failure of dermal initial lymphatics during gravitational stress (dependency), but not hypoplasia. The results reveal a pathophysiological mechanism contributing to swelling in LDS.</div></front></TEI><affiliations><list><country><li>Royaume-Uni</li></country><region><li>Angleterre</li><li>Grand Londres</li></region><settlement><li>Londres</li></settlement><orgName><li>Université de Londres</li></orgName></list><tree><country name="Royaume-Uni"><region name="Angleterre"><name sortKey="Mellor, Russell H" sort="Mellor, Russell H" uniqKey="Mellor R" first="Russell H." last="Mellor">Russell H. Mellor</name></region><name sortKey="Burnand, Kevin G" sort="Burnand, Kevin G" uniqKey="Burnand K" first="Kevin G." last="Burnand">Kevin G. Burnand</name><name sortKey="Hubert, Charlotte" sort="Hubert, Charlotte" uniqKey="Hubert C" first="Charlotte" last="Hubert">Charlotte Hubert</name><name sortKey="Jeffery, Steve" sort="Jeffery, Steve" uniqKey="Jeffery S" first="Steve" last="Jeffery">Steve Jeffery</name><name sortKey="Levick, J Rodney" sort="Levick, J Rodney" uniqKey="Levick J" first="J. Rodney" last="Levick">J. Rodney Levick</name><name sortKey="M Kinen, Taija" sort="M Kinen, Taija" uniqKey="M Kinen T" first="Taija" last="M Kinen">Taija M Kinen</name><name sortKey="Mortimer, Peter S" sort="Mortimer, Peter S" uniqKey="Mortimer P" first="Peter S." last="Mortimer">Peter S. Mortimer</name><name sortKey="Smith, Alberto" sort="Smith, Alberto" uniqKey="Smith A" first="Alberto" last="Smith">Alberto Smith</name><name sortKey="Stanton, Anthony W B" sort="Stanton, Anthony W B" uniqKey="Stanton A" first="Anthony W. B." last="Stanton">Anthony W. B. Stanton</name><name sortKey="Tate, Naomi" sort="Tate, Naomi" uniqKey="Tate N" first="Naomi" last="Tate">Naomi Tate</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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