Gα13 is part of a heterotrimeric complex (αβγ) associated with G protein-coupled receptors (GPCRs). Upon stimulation of a GPCR, the Gα subunit gets loaded with GTP and activates RHOA, which in turn becomes GTP-loaded and interacts with various effectors to regulate essential cellular functions such as cytoskeletal dynamics and organisation, polarity, trafficking, migration and cell proliferation. In melanocytes, our results show that the R200K mutation creates a constitutively active form of Gα13, independently of GPCR engagement, and triggers changes in cell morphology and function. It leads to increased actin polymerisation and higher levels of phosphorylated myosin light chains (MLCs), which enhance cell contractility. These combined effects lead to rounding of melanocytes. We traced these cellular changes to hyperactivation of RHOA and its effector ROCK, using specific inhibitors that were able to reverse the morphological changes in the cells. The R200K mutation in Gα13 also affects the transcription factor YAP, causing its nuclear translocation and increased activity to trigger transcription of the ARPC5 gene, involved in actin polymerisation.These significant changes in cell signalling and morphology strongly altered cell migration and adhesion, while cell proliferation remained unchanged. Furthermore, using melanocyte-keratinocyte co-culture experiments, we found that mutant melanocytes cannot efficiently transfer melanin to surrounding keratinocytes, explaining the pigmentation defect observed in patients.

Our results thus highlight the importance of Gα13 and RHOA in human development and their role in melanogenesis. Thanks to our experiments showing that it is possible to reverse the cellular defects triggered by this recurrent mutation through the targeted use of pharmacological inhibitors, this work offers therapeutic prospects for these patients.

Reference

El Masri R, Iannuzzo A, Kuentz P, Tacine R, Vincent M, Barbarot S, Morice-Picard F, Boralevi F, Oillarburu N, Mazereeuw-Hautier J, Duffourd Y, Faivre L, Sorlin A, Vabres P, Delon J. A postzygotic GNA13 variant upregulates the RHOA/ROCK pathway and alters melanocyte function in a mosaic skin hypopigmentation syndrome. Nature Communications. 2025 Feb 18;16(1):1751. doi: 10.1038/s41467-025-56995-4. PMID: 39966435; PMCID: PMC11836271.