Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Nature medicine, 2019-07, Vol.25 (7), p.1116-1122

Ort / Verlag

New York: Nature Publishing Group US

Erscheinungsjahr

2019

Quelle

MEDLINE

Beschreibungen/Notizen

• The treatment of lymphatic anomaly, a rare devastating disease spectrum of mostly unknown etiologies, depends on the patient manifestations 1 . Identifying the causal genes will allow for developing affordable therapies in keeping with precision medicine implementation 2 . 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. A recurrent gain-of-function mutation in ARAF causes lymphatic anomaly in two unrelated patients, and treating one of the patients with an FDA-approved MEK inhibitor resulted in a remarkable recovery, exemplifying the power of precision medicine.