Ferrell Robert E
Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
Ann N Y Acad Sci. 2002 Dec;979:39-51; discussion 76-9. doi: 10.1111/j.1749-6632.2002.tb04866.x.
The hereditary lymphedemas provide an opportunity to identify genes involved in normal and deranged lymphatic development. Genetic analysis of families with Milroy's disease identified mutations in VEGFR3 as a cause of congenital lymphedema, confirming the importance of VEGFC/VEGFR3 signaling in lymphatic development. These observations led to the identification of a mouse model for primary lymphedema, and subsequent analysis of this mouse model, using transgenic and gene transfer techniques, has provided initial clues to the development of a biologically based therapy for primary lymphedema. Of more importance from a public health perspective is the fact that manipulation of this pathway may lead to effective therapies for the more prevalent forms of secondary lymphedema. Identification of FOXC2 as the gene mutated in the lymphedema-distichiasis syndrome has revealed new molecular insight into lymphatic development. Molecular analysis of the FOXC2 pathway may provide clues to developmental pathways shared by the lymphatic system and the other developmental abnormalities associated with this complex syndrome. With improving knowledge of the human genome, genetic analysis of families with lymphedema continues to offer one of the most promising approaches to identifying genes influencing lymphatic development.
遗传性淋巴水肿为鉴定参与正常和异常淋巴管发育的基因提供了契机。对患有米尔罗伊病的家族进行基因分析，确定血管内皮生长因子受体3（VEGFR3）突变是先天性淋巴水肿的病因，证实了血管内皮生长因子C（VEGFC）/VEGFR3信号传导在淋巴管发育中的重要性。这些观察结果促成了原发性淋巴水肿小鼠模型的鉴定，随后利用转基因和基因转移技术对该小鼠模型进行分析，为开发基于生物学的原发性淋巴水肿治疗方法提供了初步线索。从公共卫生角度来看，更重要的是，操纵这一信号通路可能会为更常见的继发性淋巴水肿形式带来有效的治疗方法。FOXC2被鉴定为淋巴水肿-双行睫综合征中的突变基因，这为淋巴管发育揭示了新的分子见解。对FOXC2信号通路的分子分析可能会为淋巴系统与该复杂综合征相关的其他发育异常所共有的发育途径提供线索。随着对人类基因组认识的不断提高，对淋巴水肿家族的基因分析仍然是鉴定影响淋巴管发育基因的最具前景的方法之一。
