Abstract
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 language | English (US) |
|---|---|
| Pages (from-to) | 1116-1122 |
| Number of pages | 7 |
| Journal | Nature Medicine |
| Volume | 25 |
| Issue number | 7 |
| DOIs | |
| State | Published - Jul 1 2019 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Biochemistry, Genetics and Molecular Biology(all)
Cite this
ARAF recurrent mutation causes central conducting lymphatic anomaly treatable with a MEK inhibitor. / 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.
In: Nature Medicine, Vol. 25, No. 7, 01.07.2019, p. 1116-1122.Research output: Contribution to journal › Letter
}
TY - JOUR
T1 - ARAF recurrent mutation causes central conducting lymphatic anomaly treatable with a MEK inhibitor
AU - Li, Dong
AU - March, Michael E.
AU - Gutierrez-Uzquiza, Alvaro
AU - Kao, Charlly
AU - Seiler, Christoph
AU - Pinto, Erin
AU - Matsuoka, Leticia S.
AU - Battig, Mark R.
AU - Bhoj, Elizabeth J.
AU - Wenger, Tara L.
AU - Tian, Lifeng
AU - Robinson, Nora
AU - Wang, Tiancheng
AU - Liu, Yichuan
AU - Weinstein, Brant M.
AU - Swift, Matthew
AU - Jung, Hyun Min
AU - Kaminski, Courtney N.
AU - Chiavacci, Rosetta
AU - Perkins, Jonathan A.
AU - Levine, Michael A.
AU - Sleiman, Patrick M.A.
AU - Hicks, Patricia J.
AU - Strausbaugh, Janet T.
AU - Belasco, Jean B.
AU - Dori, Yoav
AU - Hakonarson, Hakon
PY - 2019/7/1
Y1 - 2019/7/1
N2 - 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.
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.
UR - http://www.scopus.com/inward/record.url?scp=85068441534&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85068441534&partnerID=8YFLogxK
U2 - 10.1038/s41591-019-0479-2
DO - 10.1038/s41591-019-0479-2
M3 - Letter
C2 - 31263281
AN - SCOPUS:85068441534
VL - 25
SP - 1116
EP - 1122
JO - Nature Medicine
JF - Nature Medicine
SN - 1078-8956
IS - 7
ER -