FOXC2 haploinsufficient mice are a model for human autosomal dominant lymphedema-distichiasis syndrome
FOXC2 haploinsufficient mice are a model for human autosomal dominant lymphedema-distichiasis syndrome
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DOI：
10.1093/hmg/ddg123
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发表时间：
2003-05-15
影响因子：
3.5
通讯作者：
Glover, TW
中科院分区：
文献类型：
--
作者：
Kriederman, BM;Myloyde, TL;Glover, TW
淋巴水肿-二联症(LD)(OMIM 153400)是一种罕见的常染色体显性遗传性疾病，其特征是青春期开始出现下肢淋巴水肿和异常的第二排睫毛发自眉板腺。在一些患者中，心脏、骨骼和其他缺陷共存。我们以前在受影响的LD家族成员中发现了叉头转录因子FOXC2的失活、无义和移码突变。为了进一步阐明FOXC2缺乏与该综合征的临床(和淋巴管异常增生)表型的关系，我们对杂合(+/-)小鼠的淋巴组织进行了动态淋巴成像和免疫组织化学检查，以定向干扰FOXC2。成年杂合子小鼠表现为全身性淋巴管和淋巴结增生，很少出现后肢肿胀。逆行淋巴流经明显功能不全的淋巴管瓣流入肠系膜结节、肠壁和肝脏。此外，FOXC2+/-小鼠均表现为二叉虫病。我们的结论是，FOXC2单倍体缺陷小鼠与LD患者独特的淋巴和眼部表型非常相似。此外，与LD相关的颅面部、心血管和骨骼异常有时已被证明在FOXC2基因缺失纯合子小鼠中是完全穿透的。因此，FOXC2突变小鼠为探索与间充质分化相关的分子机制和生理事件提供了理想的模型。淋巴管的生长发育和人类LD综合征的临床异常。
Lymphedema-distichiasis (LD) (OMIM 153400) is a rare autosomal-dominant condition characterized by pubertal onset of lower limb lymphedema and an aberrant second row of eyelashes arising from the meibomian glands. In some patients cardiac, skeletal and other defects coexist. We previously identified inactivating, nonsense and frameshift mutations in the forkhead transcription factor FOXC2 in affected members of LD families. To further delineate the relationship of FOXC2 deficiency to the clinical (and lymphangiodysplastic) phenotype in this syndrome, we performed dynamic lymphatic imaging and immunohistochemical examination of lymphatic tissues in mice heterozygous (+/-) for a targeted disruption of Foxc2. Adult heterozygote mice characteristically exhibited a generalized lymphatic vessel and lymph node hyperplasia and rarely exhibited hindlimb swelling. Retrograde lymph flow through apparently incompetent interlymphangion valves into the mesenteric nodes, intestinal wall and liver was also observed. In addition, Foxc2 +/- mice uniformly displayed distichiasis. We conclude that Foxc2 haploinsufficient mice mimic closely the distinctive lymphatic and ocular phenotype of LD patients. Furthermore, the craniofacial, cardiovascular and skeletal abnormalities sometimes associated with LD have previously been shown to be fully penetrant in homozygous Foxc2 null mice. This Foxc2 mutant mouse thus provides an ideal model for exploring molecular mechanisms and physiologic events in mesenchymal differentiation associated with. lymphatic growth and development and the clinical abnormalities seen in human LD syndrome.