PTPN11 Mosaicism Causes a Spectrum of Pigmentary and Vascular Neurocutaneous Disorders and Predisposes to Melanoma - INRAE - Institut national de recherche pour l’agriculture, l’alimentation et l’environnement Access content directly
Journal Articles Journal of Investigative Dermatology Year : 2022

PTPN11 Mosaicism Causes a Spectrum of Pigmentary and Vascular Neurocutaneous Disorders and Predisposes to Melanoma

Satyamaanasa Polubothu
Nicole Bender
Siobhan Muthiah
Davide Zecchin
Charalambos Demetriou
Sara Barberan Martin
Sony Malhotra
Jana Travnickova
Zhiqiang Zeng
Markus Böhm
Catherine Cottrell
  • Function : Author
Olivia Davies
Eulalia Baselga
Nigel Burrows
Virginie Carmignac
Joey Santiago Diaz
Christine Fink
Holger Haenssle
Rudolf Happle
Mark Harland
Jacquelyn Majerowski
Pierre Vabres
Marie Vincent
Julia Newton-Bishop
D. Tim Bishop
Dawn Siegel
E. Elizabeth Patton
Maya Topf
Neil Rajan
Beth Drolet

Abstract

Phakomatosis 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 vari- ants 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 over-activation 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 nevusspilus and capillary malformation syndromes, paving the way for better clinical management.
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hal-04076946 , version 1 (21-04-2023)

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Satyamaanasa Polubothu, Nicole Bender, Siobhan Muthiah, Davide Zecchin, Charalambos Demetriou, et al.. PTPN11 Mosaicism Causes a Spectrum of Pigmentary and Vascular Neurocutaneous Disorders and Predisposes to Melanoma. Journal of Investigative Dermatology, 2022, ⟨10.1016/j.jid.2022.09.661⟩. ⟨hal-04076946⟩
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