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

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. PerkinsMichael A. Levine, Patrick M.A. Sleiman, Patricia J. Hicks, Janet T. Strausbaugh, Jean B. Belasco, Yoav Dori, Hakon Hakonarson

Research output: Contribution to journalArticlepeer-review

87 Scopus citations


The treatment of lymphatic anomaly, a rare devastating disease spectrum of mostly unknown etiologies, depends on the patient manifestations1. Identifying the causal genes will allow for developing affordable therapies in keeping with precision medicine implementation2. 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 patient’s 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.

Original languageEnglish (US)
Pages (from-to)1116-1122
Number of pages7
JournalNature medicine
Issue number7
StatePublished - Jul 1 2019
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)


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