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Lookup NU author(s): Dr Siobhan Muthiah, Professor Neil RajanORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2022 The AuthorsPhakomatosis pigmentovascularis is a diagnosis that denotes the coexistence of pigmentary and vascular birthmarks of specific types, accompanied by variable multisystem involvement, including CNS disease, asymmetrical growth, and a predisposition to malignancy. Using a tight phenotypic group and high-depth next-generation sequencing of affected tissues, we discover here clonal mosaic variants in gene PTPN11 encoding SHP2 phosphatase as a cause of phakomatosis pigmentovascularis type III or spilorosea. Within an individual, the same variant is found in distinct pigmentary and vascular birthmarks and is undetectable in blood. We go on to show that the same variants can cause either the pigmentary or vascular phenotypes alone, and drive melanoma development within pigmentary lesions. Protein structure modeling highlights that although variants lead to loss of function at the level of the phosphatase domain, resultant conformational changes promote longer ligand binding. In vitro modeling of the missense variants confirms downstream MAPK pathway overactivation and widespread disruption of human endothelial cell angiogenesis. Importantly, patients with PTPN11 mosaicism theoretically risk passing on the variant to their children as the germline RASopathy Noonan syndrome with lentigines. These findings improve our understanding of the pathogenesis and biology of nevus spilus and capillary malformation syndromes, paving the way for better clinical management.
Author(s): Polubothu S, Bender N, Muthiah S, Zecchin D, Demetriou C, Martin SB, Malhotra S, Travnickova J, Zeng Z, Bohm M, Barbarot S, Cottrell C, Davies O, Baselga E, Burrows NP, Carmignac V, Diaz JS, Fink C, Haenssle HA, Happle R, Harland M, Majerowski J, Vabres P, Vincent M, Newton-Bishop JA, Bishop DT, Siegel D, Patton EE, Topf M, Rajan N, Drolet B, Kinsler VA
Publication type: Article
Publication status: Published
Journal: Journal of Investigative Dermatology
Year: 2023
Volume: 143
Issue: 6
Pages: 1042-1051.e3
Print publication date: 01/06/2023
Online publication date: 22/12/2022
Acceptance date: 22/09/2022
Date deposited: 16/02/2023
ISSN (print): 0022-202X
ISSN (electronic): 1523-1747
Publisher: Elsevier B.V.
URL: https://doi.org/10.1016/j.jid.2022.09.661
DOI: 10.1016/j.jid.2022.09.661
PubMed id: 36566878
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