Journal Article

PUBDB-2023-08102

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png PTPN11 Mosaicism Causes a Spectrum of Pigmentary and Vascular Neurocutaneous Disorders and Predisposes to Melanoma

Polubothu, S. ; Bender, N. ; Muthiah, S. ; Zecchin, D. ; Demetriou, C. ; Martin, S. B. ; Malhotra, S. ; Travnickova, J. ; Zeng, Z. ; Böhm, M. ; Barbarot, S. ; Cottrell, C. ; Davies, O. ; Baselga, E. ; Burrows, N. P. ; Carmignac, V. ; Diaz, J. S. ; Fink, C. ; Haenssle, H. A. ; Happle, R. ; Harland, M. ; Majerowski, J. ; Vabres, P. ; Vincent, M. ; Newton-Bishop, J. A. ; Bishop, D. T. ; Siegel, D. ; Patton, E. E. ; Topf, M.Extern*CSSB* ; Rajan, N. ; Drolet, B. ; Kinsler, V. A. (Corresponding author)

2023
Elsevier Amsterdam

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Please use a persistent id in citations: doi:10.1016/j.jid.2022.09.661  doi:10.3204/PUBDB-2023-08102

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 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.

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Contributing Institute(s):

1. CSSB - Leibniz-Institut für Experimentelle Virologie (LIV) / UKE - Maya Topf (CSSB-LIV/UKE-MT)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)
2. ZF-MEL-CHEMBIO - Chemical Biology in Zebrafish: Drug-Leads and New Targets in the Melanocyte Lineage and Melanoma (648489) (648489)

Experiment(s):

1. No specific instrument

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 5 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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