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Publications

Journal Article Epublish

PubMed: 39966435 DOI: 10.1038/s41467-025-56995-4

A postzygotic GNA13 variant upregulates the RHOA/ROCK pathway and alters melanocyte function in a mosaic skin hypopigmentation syndrome.

Nat Commun 16(1):1751

Authors: Rana El Masri, Alberto Iannuzzo, Paul Kuentz, Rachida Tacine, Marie Vincent, Sébastien Barbarot, Fanny Morice-Picard, Franck Boralevi, Naia Oillarburu, Juliette Mazereeuw-Hautier, Yannis Duffourd, Laurence Faivre, Arthur Sorlin, Pierre Vabres, Jérôme Delon

Affiliations

  • Université Paris Cité, CNRS, Inserm, Institut Cochin, Paris, France. Department of Cell Physiology & Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland.
  • Université Paris Cité, CNRS, Inserm, Institut Cochin, Paris, France.
  • UFR des Sciences de Santé, Inserm - Université de Bourgogne UMR1231 GAD "Génétique des Anomalies du Développement", FHU-TRANSLAD, Dijon, France.
  • Oncobiologie Génétique Bioinformatique, PCBio, Centre Hospitalier Universitaire de Besançon, Besançon, France.
  • Unité de Génétique clinique, Service de génétique médicale, CHU de Nantes - Hôpital Mère-Enfant, Nantes, France.
  • Nantes Université, Department of Dermatology, CHU Nantes, INRAE, UMR 1280, PhAN, Nantes, France.
  • MAGEC Reference Centre for Rare Genetic Skin Diseases, Paediatric Dermatology Unit, Department of Dermatology, CHU de Bordeaux - GH Pellegrin, Bordeaux, France.
  • Service de dermatologie, CHU de Toulouse - Hôpital Larrey, Toulouse, France.
  • CHU Dijon, Unité Fonctionnelle "Innovation diagnostique dans les maladies rares", FHU-TRANSLAD & Institut GIMI, Dijon, France.
  • CHU Dijon, Centre de Génétique et Centres de référence Anomalies du Développement et Déficience Intellectuelle, FHU-TRANSLAD & Institut GIMI, Dijon, France.
  • MAGEC Reference Centre for Rare Genetic Skin Diseases and Paediatric Dermatology Unit, Department of Paediatrics, University Hospital Dijon-Bourgogne, FHU-TRANSLAD & Institut GIMI, Dijon, France.
  • National Center of Genetics (NCG), Laboratoire national de santé (LNS), 1 Rue Louis Rech, Dudelange, Luxembourg.
  • UFR des Sciences de Santé, Inserm - Université de Bourgogne UMR1231 GAD "Génétique des Anomalies du Développement", FHU-TRANSLAD, Dijon, France.
  • MAGEC Reference Centre for Rare Genetic Skin Diseases and Paediatric Dermatology Unit, Department of Paediatrics, University Hospital Dijon-Bourgogne, FHU-TRANSLAD & Institut GIMI, Dijon, France.
  • Rare Disease Collaborative Network (RDCN) Adult Mosaic Disorders Clinic, St John's Institute of Dermatology, Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom.
  • Université Paris Cité, CNRS, Inserm, Institut Cochin, Paris, France.

Abstract

The genetic bases of mosaic pigmentation disorders have increasingly been identified, but these conditions remain poorly characterised, and their pathophysiology is unclear. Here, we report in four unrelated patients that a recurrent postzygotic mutation in GNA13 is responsible for a recognizable syndrome with hypomelanosis of Ito associated with developmental anomalies. GNA13 encodes Gα, a subunit of αβγ heterotrimeric G proteins coupled to specific transmembrane receptors known as G-protein coupled receptors. In-depth functional investigations revealed that this R200K mutation provides a gain of function to Gα. Mechanistically, we show that this variant hyperactivates the RHOA/ROCK signalling pathway that consequently increases actin polymerisation and myosin light chains phosphorylation, and promotes melanocytes rounding. Our results also indicate that R200K Gα hyperactivates the YAP signalling pathway. All these changes appear to affect cell migration and adhesion but not the proliferation. Our results suggest that hypopigmentation can result from a defect in melanosome transfer to keratinocytes due to cell shape alterations. These findings highlight the interaction between heterotrimeric G proteins and the RHOA pathway, and their role in melanocyte function.

MeSH

Hypopigmentation, Skin, Cells, Gtp-Binding Proteins, Biological Science Disciplines, Melanocytes, Pigmentation, Mutation