PUBLICATION
Mosaic RAS/MAPK variants cause sporadic vascular malformations which respond to targeted therapy
- Authors
- Al-Olabi, L., Polubothu, S., Dowsett, K., Andrews, K.A., Stadnik, P., Joseph, A.P., Knox, R., Pittman, A., Clark, G., Baird, W., Bulstrode, N., Glover, M., Gordon, K., Hargrave, D., Huson, S.M., Jacques, T.S., James, G., Kondolf, H., Kangesu, L., Keppler-Noreuil, K.M., Khan, A., Lindhurst, M.J., Lipson, M., Mansour, S., O'Hara, J., Mahon, C., Mosica, A., Moss, C., Murthy, A., Ong, J., Parker, V.E., Rivière, J.B., Sapp, J.C., Sebire, N.J., Shah, R., Sivakumar, B., Thomas, A., Virasami, A., Waelchli, R., Zeng, Z., Biesecker, L.G., Barnacle, A., Topf, M., Semple, R.K., Patton, E.E., Kinsler, V.A.
- ID
- ZDB-PUB-180223-43
- Date
- 2018
- Source
- The Journal of Clinical Investigation 128(4): 1496-1508 (Journal)
- Registered Authors
- Patton, E. Elizabeth
- Keywords
- Drug therapy, Molecular genetics, Signal transduction, Therapeutics, Vascular Biology
- MeSH Terms
-
- Adolescent
- Adult
- Alleles*
- Animals
- Child
- Female
- HEK293 Cells
- Human Umbilical Vein Endothelial Cells
- Humans
- Infant
- MAP Kinase Kinase 1*/genetics
- MAP Kinase Kinase 1*/metabolism
- MAP Kinase Signaling System/genetics*
- Male
- Mutation*
- Phenotype*
- Vascular Malformations*/genetics
- Vascular Malformations*/metabolism
- Vascular Malformations*/pathology
- Zebrafish
- ras Proteins*/genetics
- ras Proteins*/metabolism
- PubMed
- 29461977 Full text @ Journal of Clin. Invest.
Citation
Al-Olabi, L., Polubothu, S., Dowsett, K., Andrews, K.A., Stadnik, P., Joseph, A.P., Knox, R., Pittman, A., Clark, G., Baird, W., Bulstrode, N., Glover, M., Gordon, K., Hargrave, D., Huson, S.M., Jacques, T.S., James, G., Kondolf, H., Kangesu, L., Keppler-Noreuil, K.M., Khan, A., Lindhurst, M.J., Lipson, M., Mansour, S., O'Hara, J., Mahon, C., Mosica, A., Moss, C., Murthy, A., Ong, J., Parker, V.E., Rivière, J.B., Sapp, J.C., Sebire, N.J., Shah, R., Sivakumar, B., Thomas, A., Virasami, A., Waelchli, R., Zeng, Z., Biesecker, L.G., Barnacle, A., Topf, M., Semple, R.K., Patton, E.E., Kinsler, V.A. (2018) Mosaic RAS/MAPK variants cause sporadic vascular malformations which respond to targeted therapy. The Journal of Clinical Investigation. 128(4):1496-1508.
Abstract
Background Sporadic vascular malformations (VMs) are complex congenital anomalies of blood vessels that lead to stroke, life-threatening bleeds, disfigurement, overgrowth, and/or pain. Therapeutic options are severely limited and multi-disciplinary management remains challenging, particularly for high-flow arteriovenous malformations (AVM).
Methods To investigate the pathogenesis of sporadic intracranial and extracranial VMs in 160 children in which known genetic causes had been excluded, we sequenced DNA from affected tissue and optimised analysis for detection of low mutant allele frequency.
Results We discovered multiple mosaic activating variants in four genes of the RAS-MAPK pathway, KRAS, NRAS, BRAF, and MAP2K1, a pathway commonly activated in cancer and responsible for the germ-line RAS-opathies. These variants were more frequent in high-flow than low-flow VMs. In vitro characterisation and two transgenic zebrafish AVM models which recapitulated the human phenotype validated the pathogenesis of the mutant alleles. Importantly, treatment of AVM-BRAF mutant zebrafish with the BRAF inihibitor, Vemurafinib, restored blood flow in AVM.
Conclusions Our findings uncover a major cause of sporadic vascular malformations of different clinical types, and thereby offer the potential of personalised medical treatment by repurposing existing licensed cancer therapies.
Funding This work was funded or supported by grants from AVM Butterfly Charity, the Wellcome Trust (UK), the Medical Research Council (UK), the UK National Institute for Health Research, L'Oreal-Melanoma Research Alliance, the European Research Council, and the National Human Genome Research (US).
Errata / Notes
This article is corrected by ZDB-PUB-220906-123 .
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping