Biomaterial Database

Mutations in FOXC2 in humans (lymphoedema distichiasis syndrome) cause lymphatic dysfunction on dependency. 2011

Russell H Mellor, and Naomi Tate, and Anthony W B Stanton, and Charlotte Hubert, and Taija Mäkinen, and Alberto Smith, and Kevin G Burnand, and Steve Jeffery, and J Rodney Levick, and Peter S Mortimer

Cardiac and Vascular Sciences (Dermatology), St. George's, University of London, London, UK.

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.

UI	MeSH Term	Description	Entries
D008208	Lymphatic System	A system of organs and tissues that process and transport immune cells and LYMPH.	Lymphatic Systems
D008209	Lymphedema	Edema due to obstruction of lymph vessels or disorders of the lymph nodes.	Milroy's Disease,Congenital Familial Lymphedema,Congenital Hereditary Lymphedema,Early Onset Lymphedema,Hereditary Lymphedema,Hereditary Lymphedema 1,Hereditary Lymphedema Type I,Lymphedema, Early-Onset,Lymphedema, Hereditary, Ia,Milroy Disease,Nonne-Milroy Disease,Nonne-Milroy Lymphedema,Nonne-Milroy-Meige Disease,Primary Congenital Lymphedema,Congenital Hereditary Lymphedemas,Congenital Lymphedema, Primary,Congenital Lymphedemas, Primary,Early Onset Lymphedemas,Early-Onset Lymphedema,Early-Onset Lymphedemas,Hereditary Lymphedema 1s,Hereditary Lymphedema, Congenital,Hereditary Lymphedemas,Hereditary Lymphedemas, Congenital,Lymphedema, Congenital Hereditary,Lymphedema, Early Onset,Lymphedema, Hereditary,Lymphedema, Nonne-Milroy,Lymphedema, Primary Congenital,Lymphedemas,Lymphedemas, Congenital Hereditary,Lymphedemas, Early Onset,Lymphedemas, Early-Onset,Lymphedemas, Hereditary,Lymphedemas, Primary Congenital,Milroys Disease,Nonne Milroy Disease,Nonne Milroy Lymphedema,Nonne Milroy Meige Disease,Primary Congenital Lymphedemas
D008220	Lymphography	Radiographic study of the lymphatic system following injection of dye or contrast medium.	Lymphangiography,Lymphangiographies,Lymphographies
D008297	Male		Males
D008875	Middle Aged	An adult aged 45 - 64 years.	Middle Age
D005140	Eyelashes	The hairs which project from the edges of the EYELIDS.
D005260	Female		Females
D005528	Foot	The distal extremity of the leg in vertebrates, consisting of the tarsus (ANKLE); METATARSUS; phalanges; and the soft tissues surrounding these bones.	Feet
D005542	Forearm	Part of the upper extremity in humans and primates extending from the ELBOW to the WRIST.	Antebrachium,Antebrachiums,Forearms
D006112	Gravitation	Acceleration produced by the mutual attraction of two masses, and of magnitude inversely proportional to the square of the distance between the two centers of mass. It is also the force imparted by the earth, moon, or a planet to an object near its surface. (From NASA Thesaurus, 1988)	G Force,Gravistimulation,Gravity,Force, G,G Forces,Gravities