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

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 () and Jérôme Delon ()
Additional contact information
Rana El Masri: Institut Cochin
Alberto Iannuzzo: Institut Cochin
Paul Kuentz: FHU-TRANSLAD
Rachida Tacine: Institut Cochin
Marie Vincent: CHU de Nantes - Hôpital Mère-Enfant
Sébastien Barbarot: PhAN
Fanny Morice-Picard: CHU de Bordeaux - GH Pellegrin
Franck Boralevi: CHU de Bordeaux - GH Pellegrin
Naia Oillarburu: CHU de Toulouse - Hôpital Larrey
Juliette Mazereeuw-Hautier: CHU de Toulouse - Hôpital Larrey
Yannis Duffourd: FHU-TRANSLAD
Laurence Faivre: FHU-TRANSLAD
Arthur Sorlin: FHU-TRANSLAD
Pierre Vabres: FHU-TRANSLAD
Jérôme Delon: Institut Cochin

Nature Communications, 2025, vol. 16, issue 1, 1-15

Abstract: 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 Gα13, 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 Gα13. 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 Gα13 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.

Date: 2025
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DOI: 10.1038/s41467-025-56995-4

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