Mutations in FOXC2 in Humans (Lymphoedema Distichiasis Syndrome) Cause Lymphatic Dysfunction on Dependency
Mutations in FOXC2 in Humans (Lymphoedema Distichiasis Syndrome) Cause Lymphatic Dysfunction on Dependency
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DOI：
10.1159/000323484
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发表时间：
2011-01-01
影响因子：
1.7
通讯作者：
Mortimer, Peter S.
中科院分区：
文献类型：
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作者：
Mellor, Russell H.;Tate, Naomi;Mortimer, Peter S.
背景：人类淋巴水肿双列吸虫病综合征（LDS）是由转录因子FOXC 2的种系突变引起的。在小鼠模型中，观察到缺乏淋巴和静脉瓣膜，加上异常平滑肌细胞募集到初始血管。我们研究了FOXC 2突变的人类淋巴水肿的机制，特别是重力对真皮淋巴功能的影响。研究方法：我们进行了（1）定量荧光显微淋巴管造影（FML）的皮肤前臂（非肿胀区）在心脏水平，和脚（肿胀区）低于心脏水平（依赖），然后在心脏水平，（2）免疫组化染色的微淋巴细胞在前臂和脚皮肤活检，使用抗体podoplanin，LYVE-1和平滑肌肌动蛋白。结果如下：FML显示，在依赖性期间，LDS足中初始透析液的液体摄取显著减少，但在心脏水平和LDS前臂的同一足中正常摄取（与对照组相似）。在对照组中，依赖性不损害初始淋巴充盈。免疫组化微淋巴管密度在前臂和足部没有显着差异LDS和对照组。结论：FOXC 2突变导致重力应激（依赖性）时真皮初始发育的功能衰竭，但不是发育不全。结果揭示了导致LDS肿胀的病理生理机制。版权所有（C）2011 S. Karger AG，巴塞尔
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. Copyright (C) 2011 S. Karger AG, Basel