title: Mutations in FOXC2 in humans (lymphoedema distichiasis syndrome) cause lymphatic dysfunction on dependency.
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 the foot (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 microlymphatic 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.
authors.affiliation: Cardiac and Vascular Sciences (Dermatology), St. George's, University of London, London, UK.
authors.forename: Russell H
authors.initials: RH
authors.lastname: Mellor
authors.forename: Naomi
authors.initials: N
authors.lastname: Tate
authors.forename: Anthony W B
authors.initials: AW
authors.lastname: Stanton
authors.forename: Charlotte
authors.initials: C
authors.lastname: Hubert
authors.forename: Taija
authors.initials: T
authors.lastname: Mäkinen
authors.forename: Alberto
authors.initials: A
authors.lastname: Smith
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Burnand
authors.forename: Steve
authors.initials: S
authors.lastname: Jeffery
authors.forename: J Rodney
authors.initials: JR
authors.lastname: Levick
authors.forename: Peter S
authors.initials: PS
authors.lastname: Mortimer
mesh_terms: D000328:Adult; D001706:Biopsy; D005140:Eyelashes / Q000002:abnormalities / Q000000981:diagnostic imaging / Q000473:pathology; D005260:Female; D005528:Foot; D005542:Forearm; D051858:Forkhead Transcription Factors / Q000235:genetics*; D018095:Germ-Line Mutation; D006112:Gravitation; D006801:Humans; D008208:Lymphatic System / Q000473:pathology* / Q000502:physiology*; D008209:Lymphedema / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology*; D008220:Lymphography; D008297:Male; D008875:Middle Aged; D013312:Stress, Physiological; D055815:Young Adult
chemical_list: D051858:Forkhead Transcription Factors; C082078:mesenchyme fork head 1 protein