{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T01:53:30Z","timestamp":1792461210262,"version":"4.5.0"},"reference-count":36,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"14","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Circulation"],"published-print":{"date-parts":[[2007,4,10]]},"abstract":"<jats:p>\n            <jats:bold>\n              <jats:italic>Background\u2014<\/jats:italic>\n            <\/jats:bold>\n            Mutations in the\n            <jats:italic>FOXC2<\/jats:italic>\n            gene cause lymphedema distichiasis, an inherited primary lymphedema in which a significant number of patients have varicose veins. Because lymphedema distichiasis is believed to be caused by lymphatic valve failure (reflux), and FOXC2 is highly expressed on venous valves in mouse embryos, we tested the hypothesis that\n            <jats:italic>FOXC2<\/jats:italic>\n            mutations may be linked to venous valve failure and reflux.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>\n              <jats:italic>Methods and Results\u2014<\/jats:italic>\n            <\/jats:bold>\n            The venous system of the leg was investigated with Duplex ultrasound. Pathological reflux was recorded by color Duplex ultrasound in all 18 participants with a\n            <jats:italic>FOXC2<\/jats:italic>\n            mutation, including 3 without lymphedema. Every participant with a mutation in\n            <jats:italic>FOXC2<\/jats:italic>\n            showed reflux in the great saphenous vein (n=18), compared with only 1 of 12 referents (including 10 family members;\n            <jats:italic>P<\/jats:italic>\n            &lt;0.0001, Fisher exact test). Deep vein reflux was recorded in 14 of 18 participants.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>\n              <jats:italic>Conclusions\u2014<\/jats:italic>\n            <\/jats:bold>\n            <jats:italic>FOXC2<\/jats:italic>\n            is the first gene in which mutations have been strongly associated with primary venous valve failure in both the superficial and deep veins in the lower limb. This gene appears to be important for the normal development and maintenance of venous and lymphatic valves.\n          <\/jats:p>","DOI":"10.1161\/circulationaha.106.675348","type":"journal-article","created":{"date-parts":[[2007,3,20]],"date-time":"2007-03-20T00:36:36Z","timestamp":1174350996000},"page":"1912-1920","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":183,"title":["Mutations in\n            <i>FOXC2<\/i>\n            Are Strongly Associated With Primary Valve Failure in Veins of the Lower Limb"],"prefix":"10.1161","volume":"115","author":[{"given":"Russell H.","family":"Mellor","sequence":"first","affiliation":[{"name":"From Cardiac &amp; Vascular Sciences (Dermatology) (R.H.M, A.W.B.S, P.S.M.), Clinical Genetics (G.B.), Clinical Developmental Sciences (S.J.), and Physiology (J.R.L.), St George\u2019s, University of London, London, UK; Vascular Laboratory (J.F.), St George\u2019s Hospital, London, UK; and Department of Academic Surgery (A.S, K.G.B.), St Thomas\u2019 Hospital, London, UK. Dr Mellor, G. Brice, Dr Smith, Prof Jeffery, Prof Burnand, and Prof Mortimer represent the Lymphoedema Research Consortium."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Glen","family":"Brice","sequence":"additional","affiliation":[{"name":"From Cardiac &amp; Vascular Sciences (Dermatology) (R.H.M, A.W.B.S, P.S.M.), Clinical Genetics (G.B.), Clinical Developmental Sciences (S.J.), and Physiology (J.R.L.), St George\u2019s, University of London, London, UK; Vascular Laboratory (J.F.), St George\u2019s Hospital, London, UK; and Department of Academic Surgery (A.S, K.G.B.), St Thomas\u2019 Hospital, London, UK. Dr Mellor, G. Brice, Dr Smith, Prof Jeffery, Prof Burnand, and Prof Mortimer represent the Lymphoedema Research Consortium."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anthony W.B.","family":"Stanton","sequence":"additional","affiliation":[{"name":"From Cardiac &amp; Vascular Sciences (Dermatology) (R.H.M, A.W.B.S, P.S.M.), Clinical Genetics (G.B.), Clinical Developmental Sciences (S.J.), and Physiology (J.R.L.), St George\u2019s, University of London, London, UK; Vascular Laboratory (J.F.), St George\u2019s Hospital, London, UK; and Department of Academic Surgery (A.S, K.G.B.), St Thomas\u2019 Hospital, London, UK. Dr Mellor, G. Brice, Dr Smith, Prof Jeffery, Prof Burnand, and Prof Mortimer represent the Lymphoedema Research Consortium."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jane","family":"French","sequence":"additional","affiliation":[{"name":"From Cardiac &amp; Vascular Sciences (Dermatology) (R.H.M, A.W.B.S, P.S.M.), Clinical Genetics (G.B.), Clinical Developmental Sciences (S.J.), and Physiology (J.R.L.), St George\u2019s, University of London, London, UK; Vascular Laboratory (J.F.), St George\u2019s Hospital, London, UK; and Department of Academic Surgery (A.S, K.G.B.), St Thomas\u2019 Hospital, London, UK. Dr Mellor, G. Brice, Dr Smith, Prof Jeffery, Prof Burnand, and Prof Mortimer represent the Lymphoedema Research Consortium."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alberto","family":"Smith","sequence":"additional","affiliation":[{"name":"From Cardiac &amp; Vascular Sciences (Dermatology) (R.H.M, A.W.B.S, P.S.M.), Clinical Genetics (G.B.), Clinical Developmental Sciences (S.J.), and Physiology (J.R.L.), St George\u2019s, University of London, London, UK; Vascular Laboratory (J.F.), St George\u2019s Hospital, London, UK; and Department of Academic Surgery (A.S, K.G.B.), St Thomas\u2019 Hospital, London, UK. Dr Mellor, G. Brice, Dr Smith, Prof Jeffery, Prof Burnand, and Prof Mortimer represent the Lymphoedema Research Consortium."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steve","family":"Jeffery","sequence":"additional","affiliation":[{"name":"From Cardiac &amp; Vascular Sciences (Dermatology) (R.H.M, A.W.B.S, P.S.M.), Clinical Genetics (G.B.), Clinical Developmental Sciences (S.J.), and Physiology (J.R.L.), St George\u2019s, University of London, London, UK; Vascular Laboratory (J.F.), St George\u2019s Hospital, London, UK; and Department of Academic Surgery (A.S, K.G.B.), St Thomas\u2019 Hospital, London, UK. Dr Mellor, G. Brice, Dr Smith, Prof Jeffery, Prof Burnand, and Prof Mortimer represent the Lymphoedema Research Consortium."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Rodney","family":"Levick","sequence":"additional","affiliation":[{"name":"From Cardiac &amp; Vascular Sciences (Dermatology) (R.H.M, A.W.B.S, P.S.M.), Clinical Genetics (G.B.), Clinical Developmental Sciences (S.J.), and Physiology (J.R.L.), St George\u2019s, University of London, London, UK; Vascular Laboratory (J.F.), St George\u2019s Hospital, London, UK; and Department of Academic Surgery (A.S, K.G.B.), St Thomas\u2019 Hospital, London, UK. Dr Mellor, G. Brice, Dr Smith, Prof Jeffery, Prof Burnand, and Prof Mortimer represent the Lymphoedema Research Consortium."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin G.","family":"Burnand","sequence":"additional","affiliation":[{"name":"From Cardiac &amp; Vascular Sciences (Dermatology) (R.H.M, A.W.B.S, P.S.M.), Clinical Genetics (G.B.), Clinical Developmental Sciences (S.J.), and Physiology (J.R.L.), St George\u2019s, University of London, London, UK; Vascular Laboratory (J.F.), St George\u2019s Hospital, London, UK; and Department of Academic Surgery (A.S, K.G.B.), St Thomas\u2019 Hospital, London, UK. Dr Mellor, G. Brice, Dr Smith, Prof Jeffery, Prof Burnand, and Prof Mortimer represent the Lymphoedema Research Consortium."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter S.","family":"Mortimer","sequence":"additional","affiliation":[{"name":"From Cardiac &amp; Vascular Sciences (Dermatology) (R.H.M, A.W.B.S, P.S.M.), Clinical Genetics (G.B.), Clinical Developmental Sciences (S.J.), and Physiology (J.R.L.), St George\u2019s, University of London, London, UK; Vascular Laboratory (J.F.), St George\u2019s Hospital, London, UK; and Department of Academic Surgery (A.S, K.G.B.), St Thomas\u2019 Hospital, London, UK. Dr Mellor, G. Brice, Dr Smith, Prof Jeffery, Prof Burnand, and Prof Mortimer represent the Lymphoedema Research Consortium."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_2_1_2","first-page":"114","volume":"15","year":"1996","unstructured":"Thulesius O. The venous wall and valvular function in chronic venous insufficiency. Int Angiol. 1996; 15: 114\u2013118.","journal-title":"Int Angiol"},{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1177\/000331970405500510"},{"key":"e_1_3_2_3_2","unstructured":"Tibbs DJ Sabiston DC Davies MG Mortimer PS Scurr JH. Varicose Veins Venous Disorders and Lymphatic Problems in the Lower Limb. Oxford United Kingdom; Oxford University Press; 1997."},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1136\/jech.53.3.149"},{"key":"e_1_3_2_5_2","unstructured":"Laing W. Chronic Venous Diseases of the Leg: Report No. 108. London UK: Office of Health Economics; 1992; 28: 1\u201344."},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.atv.0000107080.48969.64"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0895-4356(02)00518-8"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1524-4725.1994.tb01631.x"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2004.024075"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1007\/s004390100528"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1086\/316915"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddg123"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.907301"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(93)81785-X"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ydbio.2004.03.034"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1094"},{"key":"e_1_3_2_17_2","doi-asserted-by":"publisher","DOI":"10.1006\/dbio.1999.9382"},{"key":"e_1_3_2_18_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.modgep.2004.07.004"},{"key":"e_1_3_2_19_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/10.11.1185"},{"key":"e_1_3_2_20_2","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.39.7.478"},{"key":"e_1_3_2_21_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddi295"},{"key":"e_1_3_2_22_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1535-6108(02)00051-X"},{"key":"e_1_3_2_23_2","doi-asserted-by":"publisher","DOI":"10.1101\/gad.975002"},{"key":"e_1_3_2_24_2","doi-asserted-by":"publisher","DOI":"10.1002\/aja.1000010310"},{"key":"e_1_3_2_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/0140-6736(93)92989-7"},{"key":"e_1_3_2_26_2","doi-asserted-by":"publisher","DOI":"10.1002\/bjs.1800811108"},{"key":"e_1_3_2_27_2","doi-asserted-by":"publisher","DOI":"10.1148\/radiol.2282020411"},{"key":"e_1_3_2_28_2","doi-asserted-by":"publisher","DOI":"10.1002\/bjs.1800840113"},{"key":"e_1_3_2_29_2","doi-asserted-by":"publisher","DOI":"10.1161\/01.CIR.102.1.126"},{"key":"e_1_3_2_30_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0741-5214(95)70109-5"},{"key":"e_1_3_2_31_2","first-page":"81","volume":"33","year":"1997","unstructured":"Waksman Y, Mashiah A, Hod I, Rose SS, Friedman A. Collagen subtype pattern in normal and varicose saphenous veins in humans. Isr J Med Sci. 1997; 33: 81\u201386.","journal-title":"Isr J Med Sci"},{"key":"e_1_3_2_32_2","doi-asserted-by":"publisher","DOI":"10.1024\/0301-1526.34.3.170"},{"key":"e_1_3_2_33_2","first-page":"181","volume":"21","year":"1990","unstructured":"Budd TW, Meenaghan MA, Wirth J, Taheri SA. Histopathology of veins and venous valves of patients with venous insufficiency syndrome: ultrastructure. J Med. 1990; 21: 181\u2013199.","journal-title":"J Med"},{"key":"e_1_3_2_34_2","doi-asserted-by":"publisher","DOI":"10.1007\/s100169900133"},{"key":"e_1_3_2_35_2","doi-asserted-by":"publisher","DOI":"10.1002\/aja.1000030205"},{"key":"e_1_3_2_36_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jvs.2005.05.007"}],"container-title":["Circulation"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/CIRCULATIONAHA.106.675348","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T05:04:05Z","timestamp":1715576645000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/CIRCULATIONAHA.106.675348"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2007,4,10]]},"references-count":36,"journal-issue":{"issue":"14","published-print":{"date-parts":[[2007,4,10]]}},"alternative-id":["10.1161\/CIRCULATIONAHA.106.675348"],"URL":"https:\/\/doi.org\/10.1161\/circulationaha.106.675348","relation":{},"ISSN":["0009-7322","1524-4539"],"issn-type":[{"value":"0009-7322","type":"print"},{"value":"1524-4539","type":"electronic"}],"subject":[],"published":{"date-parts":[[2007,4,10]]},"assertion":[{"value":"2007-03-19","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}