ARAF复发突变导致中央传导性淋巴异常，可使用MEK抑制剂治疗，这一成果由费城儿童医院Hakon Hakonarson研究小组取得。 这一成果发表在2019年7月出版的国际学术期刊《自然—医学》上。

该研究团队在一个患有晚期异常淋巴疾病，对常规西罗莫司治疗无反应的12岁男孩上确定了一种可循环获得功能性ARAF突变（c.640T>C:p.S214P），该突变导致保守磷酸化位点的丧失。细胞转导ARAF-S214P显示增高的ERK1/2活动,以及淋巴管生成能力。使用MEK抑制剂曲米替尼对肌动蛋白骨架和VE-钙粘蛋白连接进行拆卸，通过在斑马鱼模型中重建淋巴表型，拯救MEK抑制剂的异常表型来验证突变的功能相关性。随后用MEK抑制剂治疗，临床症状得到显着改善，患者淋巴系统重塑，淋巴水肿消退，肺功能检查显着改善，补充氧需求停止，日常活动接近正常化。他们的结果提供了一个代表性的证明，表明遗传分类和机制理解的知识如何指导基于生物学的医学治疗，在他们的实例中拯救了生命。

据介绍，治疗淋巴异常，这是一种罕见的毁灭性疾病，主要病因不明且病人个体差异大。鉴定相关调控基因将允许开发经济实惠的疗法，并实施精确的医学治疗。

附：英文原文

Title: ARAF recurrent mutation causes central conducting lymphatic anomaly treatable with a MEK inhibitor

Author: Dong Li, Michael E. March, Alvaro Gutierrez-Uzquiza, Charlly Kao, Christoph Seiler, Erin Pinto, Leticia S. Matsuoka, Mark R. Battig, Elizabeth J. Bhoj, Tara L. Wenger, Lifeng Tian, Nora Robinson, Tiancheng Wang, Yichuan Liu, Brant M. Weinstein, Matthew Swift, Hyun Min Jung, Courtney N. Kaminski, Rosetta Chiavacci, Jonathan A. Perkins, Michael A. Levine, Patrick M. A. Sleiman, Patricia J. Hicks, Janet T. Strausbaugh, Jean B. Belasco, Yoav Dori, Hakon Hakonarson

Issue&Volume:Volume 25 Issue 7, July 2019

Abstract: The treatment of lymphatic anomaly, a rare devastating disease spectrum of mostly unknown etiologies, depends on the patient manifestations. Identifying the causal genes will allow for developing affordable therapies in keeping with precision medicine implementation. Here we identified a recurrent gain-of-function ARAF mutation (c.640T>C:p.S214P) in a 12-year-old boy with advanced anomalous lymphatic disease unresponsive to conventional sirolimus therapy and in another, unrelated, adult patient. The mutation led to loss of a conserved phosphorylation site. Cells transduced with ARAF-S214P showed elevated ERK1/2 activity, enhanced lymphangiogenic capacity, and disassembly of actin skeleton and VE-cadherin junctions, which were rescued using the MEK inhibitor trametinib. The functional relevance of the mutation was also validated by recreating a lymphatic phenotype in a zebrafish model, with rescue of the anomalous phenotype using a MEK inhibitor. Subsequent therapy of the lead proband with a MEK inhibitor led to dramatic clinical improvement, with remodeling of the patients lymphatic system with resolution of the lymphatic edema, marked improvement in his pulmonary function tests, cessation of supplemental oxygen requirements and near normalization of daily activities. Our results provide a representative demonstration of how knowledge of genetic classification and mechanistic understanding guides biologically based medical treatments, which in our instance was life-saving.

DOI: 10.1038/s41591-019-0479-2

Source:https://www.nature.com/articles/s41591-019-0479-2