ARAF recurrent mutation causes central conducting lymphatic anomaly treatable with a MEK inhibitor
2019
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 medicineimplementation2. Here we identified a recurrent gain-of-function
ARAFmutation (c.640T>C:p.S214P) in a 12-year-old boy with advanced anomalous
lymphatic diseaseunresponsive to conventional
sirolimustherapy 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-cadherinjunctions, 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 inhibitorled to dramatic clinical improvement, with remodeling of the patient’s
lymphatic systemwith 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.
Keywords:
-
Correction
-
Source
-
Cite
-
Save
46
References
57
Citations
NaN
KQI