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

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<sub>13</sub>, 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<sub>13</sub>. 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<sub>13</sub> 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.

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Publication Details

Journal
Nature Communications
Published
2025-02-18
DOI
https://doi.org/10.1038/s41467-025-56995-4
Citations
4
Primary Topic
Hippo pathway signaling and YAP/TAZ
Type
article
Field-Weighted Citation Impact
4.61

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article

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

Paul Kuentz, Laurence Olivier Faivre, Rana El Masri, S. Barbarot et al.
4 citations
Nature Communications
Hippo pathway signaling and YAP/TAZ
4.61
article

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

Paul Kuentz, Laurence Olivier Faivre, Rana El Masri, S. Barbarot, Fanny Morice‐Picard, Rachida Tacine, P. Vabres, Arthur Sorlin, J. Mazereeuw‐Hautier, Marie Vincent, Jérôme Delon, F. Boralévi, Alberto Iannuzzo, Naia Oillarburu, Yannis Duffourd
article en
4 citations

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<sub>13</sub>, 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<sub>13</sub>. 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<sub>13</sub> 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.

Nature CommunicationsVol. 16(1)
University of Geneva (CH), Centre National de la Recherche Scientifique (FR), Inserm (FR), Université de Bourgogne (FR), Guy's and St Thomas' NHS Foundation Trust (GB), Université Paris Cité (FR), Centre Hospitalier Universitaire de Bordeaux (FR), Centre Hospitalier Universitaire de Nantes (FR), Centre Hospitalier Universitaire de Toulouse (FR), Centre Hospitalier Universitaire de Besançon (FR), Institut National de Recherche pour l'Agriculture, l'Alimentation et l'Environnement (FR), CHU Dijon Bourgogne (FR), Genomic and Immunotherapy Medical Institute (FR), Hôpital Larrey (FR), Hôpital Mère-Enfant (FR), Institut Cochin (FR), Laboratoire National de Santé (LU), PhysioPathologie des Adaptations Nutritionnelles (FR), Nantes Université (FR)
Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, Fondation pour la Recherche Médicale, European Society for Immunodeficiencies, Inserm Transfert
Life in Land
Openalex Percentile: Top 7%
Hippo pathway signaling and YAP/TAZ
4.61
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