Pawlikowski, J.S. et al. (2015) Acute inhibition of MEK suppresses congenital melanocytic nevus syndrome in a murine model driven by activated NRAS and Wnt signaling. Journal of Investigative Dermatology, 135(8), pp. 2093-2101. (doi: 10.1038/jid.2015.114) (PMID:25815427) (PMCID:PMC4539947)
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Abstract
Congenital melanocytic nevus (CMN) syndrome is the association of pigmented melanocytic nevi with extra-cutaneous features, classically melanotic cells within the central nervous system, most frequently caused by a mutation of NRAS codon 61. This condition is currently untreatable and carries a significant risk of melanoma within the skin, brain, or leptomeninges. We have previously proposed a key role for Wnt signaling in the formation of melanocytic nevi, suggesting that activated Wnt signaling may be synergistic with activated NRAS in the pathogenesis of CMN syndrome. Some familial pre-disposition suggests a germ-line contribution to CMN syndrome, as does variability of neurological phenotypes in individuals with similar cutaneous phenotypes. Accordingly, we performed exome sequencing of germ-line DNA from patients with CMN to reveal rare or undescribed Wnt-signaling alterations. A murine model harboring activated NRASQ61K and Wnt signaling in melanocytes exhibited striking features of CMN syndrome, in particular neurological involvement. In the first model of treatment for this condition, these congenital, and previously assumed permanent, features were profoundly suppressed by acute post-natal treatment with a MEK inhibitor. These data suggest that activated NRAS and aberrant Wnt signaling conspire to drive CMN syndrome. Post-natal MEK inhibition is a potential candidate therapy for patients with this debilitating condition.
| Item Type: | Articles |
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| Additional Information: | An addendum to this work can be found at https://doi.org/10.1038/jid.2015.230. |
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Blyth, Professor Karen and King, Dr Ayala and Nixon, Mr Colin and Mullin, Mr James and Lambie, Mrs Wendy and Reid, Mrs Claire and Holmes, Dr William and McGregor, Dr Fiona and Adams, Professor Peter |
| Authors: | Pawlikowski, J.S., Brock, C., Chen, S.-C., Al-Olabi, L., Nixon, C., McGregor, F., Paine, S., Chanudet, E., Lambie, W., Holmes, W.M., Mullin, J.M., Richmond, A., Wu, H., Blyth, K., King, A., Kinsler, V.A., and Adams, P.D. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences College of Medical Veterinary and Life Sciences > School of Psychology & Neuroscience |
| Journal Name: | Journal of Investigative Dermatology |
| Journal Abbr.: | JID |
| Publisher: | Nature Publishing Group |
| ISSN: | 0022-202X |
| ISSN (Online): | 1523-1747 |
| Copyright Holders: | Copyright © 2015 The Society for Investigative Dermatology |
| First Published: | First published in Journal of Investigative Dermatology 135(8):2093-2101 |
| Publisher Policy: | Reproduced under a Creative Commons License |
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