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; Sebastien Barbarot; Catherine Cottrell; Olivia Davies; Eulalia Baselga; Nigel P. Burrows; Virginie Carmignac; Joey Santiago Diaz; Christine Fink; Holger A. Haenssle; Rudolf Happle; Mark Harland; Jacquelyn Majerowski; Pierre Vabres; Marie Vincent; Julia A. Newton-Bishop; D. Tim Bishop; Dawn Siegel; E. Elizabeth Patton; Maya Topf; Neil Rajan; Beth Drolet; Veronica A. Kinsler

doi:10.1016/j.jid.2022.09.661

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

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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, …

Journal of investigative dermatology, Vol.143(6), pp.1042-1051.e3

01/06/2023

DOI: https://doi.org/10.1016/j.jid.2022.09.661

PMID: 36566878

Résumé

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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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Titre: PTPN11 Mosaicism Causes a Spectrum of Pigmentary and Vascular Neurocutaneous Disorders and Predisposes to Melanoma
Créateurs - sans rôle: Satyamaanasa Polubothu - The Francis Crick Institute
Nicole Bender - Department of Dermatology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
Siobhan Muthiah - Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
Davide Zecchin - Mosaicism and Precision Medicine Laboratory, The Francis Crick Institute, London, United Kingdom
Charalambos Demetriou - Mosaicism and Precision Medicine Laboratory, The Francis Crick Institute, London, United Kingdom
Sara Barberan Martin - Mosaicism and Precision Medicine Laboratory, The Francis Crick Institute, London, United Kingdom
Sony Malhotra - Research Complex at Harwell
Jana Travnickova - MRC Human Genetics Unit and Cancer Research UK Edinburgh Centre, MRC Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
Zhiqiang Zeng - MRC Human Genetics Unit and Cancer Research UK Edinburgh Centre, MRC Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
Markus Böhm - Department of Dermatology, University of Münster, Münster, Germany
Sebastien Barbarot - Department of Dermatology, Centre Hospitalier Universitaire Nantes, Nantes, France
Catherine Cottrell - Institute for Genomic Medicine, Nationwide Childrens’ Hospital, Columbus, USA
Olivia Davies - Department of Dermatology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
Eulalia Baselga - Department of Dermatology, SJD Barcelona Children's Hospital, Barcelona, Spain
Nigel P. Burrows - Department of Dermatology, Addenbrooke’s Hospital, Cambridge, United Kingdom
Virginie Carmignac - Université de Bourgogne
Joey Santiago Diaz - Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, Cancer Research UK Clinical Centre at Leeds, St James's University Hospital, Leeds, United Kingdom
Christine Fink - Department of Dermatology, University of Heidelberg, Heidelberg, Germany
Holger A. Haenssle - Department of Dermatology, University of Heidelberg, Heidelberg, Germany
Rudolf Happle - Department of Dermatology, Medical Center, University of Freiburg, Freiburg, Germany
Mark Harland - Section of Epidemiology and Biostatistics, Leeds Institute of Cancer and Pathology, Cancer Research UK Clinical Centre at Leeds, St James's University Hospital, Leeds, United Kingdom
Jacquelyn Majerowski - Department of Dermatology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
Pierre Vabres - Génétique des Anomalies du Développement, Université de Bourgogne, Dijon, France
Marie Vincent - Department of Dermatology, Centre Hospitalier Universitaire Nantes, Nantes, France
Julia A. Newton-Bishop - Division of Haematology and Immunology, Leeds Institute of Medical Research, Leeds, United Kingdom
D. Tim Bishop - Division of Haematology and Immunology, Leeds Institute of Medical Research, Leeds, United Kingdom
Dawn Siegel - Department of Dermatology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
E. Elizabeth Patton - MRC Human Genetics Unit and Cancer Research UK Edinburgh Centre, MRC Institute of Genetics & Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom
Maya Topf - Centre for Structural Systems Biology, Leibniz-Institut für Virologie (LIV) and Universitätsklinikum Hamburg-Eppendorf (UKE), Hamburg, Germany
Neil Rajan - Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
Beth Drolet - Department of Dermatology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
Veronica A. Kinsler - The Francis Crick Institute
Détails de publication: Journal of investigative dermatology, Vol.143(6), pp.1042-1051.e3
Éditeur: Elsevier Inc
Identifiants: 99158882209311
Unité académique: Physiologie et Médecine Expérimentale du coeur et des muscles - PhyMedExp
Langue: English
Type de ressource: Journal article