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

Li, D., March, M.E., Gutierrez-Uzquiza, A., Kao, C., Seiler, C., Pinto, E., Matsuoka, L.S., Battig, M.R., Bhoj, E.J., Wenger, T.L., Tian, L., Robinson, N., Wang, T., Liu, Y., Weinstein, B.M., Swift, M., Jung, H.M., Kaminski, C.N., Chiavacci, R., Perkins, J.A., Levine, M.A., Sleiman, P.M.A., Hicks, P.J., Strausbaugh, J.T., Belasco, J.B., Dori, Y., Hakonarson, H.
Nature medicine   25(7): 1116-1122 (Journal)
Registered Authors
Jung, Hyun Min, Li, Dong, Seiler, Christoph, Swift, Matthew Russell, Weinstein, Brant M.
MeSH Terms
  • Adult
  • Animals
  • Child
  • Female
  • HEK293 Cells
  • Humans
  • Lymphatic Abnormalities/drug therapy
  • Lymphatic Abnormalities/genetics*
  • Male
  • Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors*
  • Mutation*
  • Proto-Oncogene Proteins A-raf/genetics*
  • Pyridones/therapeutic use*
  • Pyrimidinones/therapeutic use*
  • Whole Exome Sequencing
  • Zebrafish
31263281 Full text @ Nat. Med.
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.
Genes / Markers
Show all Figures
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes