RT Journal Article
T1 ARAF recurrent mutation causes central conducting lymphatic anomaly treatable with a MEK inhibitor
A1 Li, Dong
A1 March, Michael E.
A1 Gutiérrez Uzquiza, Álvaro
A1 Kao, Charlly
A1 Seiler, Christoph
A1 Pinto, Erin
A1 Matsuoka, Leticia S.
A1 Battig, Mark R.
A1 Bhoj, Elizabeth J.
A1 Wenger, Tara L.
A1 Tian, Lifeng
A1 Robinson, Nora
A1 Wang, Tiancheng
A1 Liu, Yichuan
A1 Weinstein, Brant M.
A1 Swift, Matthew
A1 Jung, Hyun Min
A1 Kaminski, Courtney N.
A1 Chiavacci, Rosetta
A1 Perkins, Jonathan A.
A1 Levine, Michael A.
A1 Sleiman, Patrick M. A.
A1 Hicks, Patricia J.
A1 Strausbaugh, Janet T.
A1 Belasco, Jean B.
A1 Dori, Yoav
A1 Hakonarson, Hakon
AB 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
SN 1078-8956
SN 1546-170X
YR 2019
FD 2019-07
LK https://hdl.handle.net/20.500.14352/115122
UL https://hdl.handle.net/20.500.14352/115122
LA eng
NO Li D, March ME, Gutierrez-Uzquiza A, Kao C, Seiler C, Pinto E, et al. ARAF recurrent mutation causes central conducting lymphatic anomaly treatable with a MEK inhibitor. Nat Med [Internet]. julio de 2019 [citado 20 de enero de 2025];25(7):1116-22. Disponible en: https://www.nature.com/articles/s41591-019-0479-2
DS Docta Complutense
RD 21 abr 2025