Mosaic Activating Mutations in GNA11 and GNAQ Are Associated with Phakomatosis Pigmentovascularis and Extensive Dermal Melanocytosis.

Fiche publication

Date publication

avril 2016


The Journal of investigative dermatology


Membres identifiés du Cancéropôle Est :
Pr VABRES Pierre

Tous les auteurs :
Thomas AC, Zeng Z, Rivière JB, O'Shaughnessy R, Al-Olabi L, St-Onge J, Atherton DJ, Aubert H, Bagazgoitia L, Barbarot S, Bourrat E, Chiaverini C, Chong WK, Duffourd Y, Glover M, Groesser L, Hadj-Rabia S, Hamm H, Happle R, Mushtaq I, Lacour JP, Waelchli R, Wobser M, Vabres P, Patton EE, Kinsler VA


Common birthmarks can be an indicator of underlying genetic disease but are often overlooked. Mongolian blue spots (dermal melanocytosis) are usually localized and transient, but they can be extensive, permanent, and associated with extracutaneous abnormalities. Co-occurrence with vascular birthmarks defines a subtype of phakomatosis pigmentovascularis, a group of syndromes associated with neurovascular, ophthalmological, overgrowth, and malignant complications. Here, we discover that extensive dermal melanocytosis and phakomatosis pigmentovascularis are associated with activating mutations in GNA11 and GNAQ, genes that encode Gα subunits of heterotrimeric G proteins. The mutations were detected at very low levels in affected tissues but were undetectable in the blood, indicating that these conditions are postzygotic mosaic disorders. In vitro expression of mutant GNA11(R183C) and GNA11(Q209L) in human cell lines demonstrated activation of the downstream p38 MAPK signaling pathway and the p38, JNK, and ERK pathways, respectively. Transgenic mosaic zebrafish models expressing mutant GNA11(R183C) under promoter mitfa developed extensive dermal melanocytosis recapitulating the human phenotype. Phakomatosis pigmentovascularis and extensive dermal melanocytosis are therefore diagnoses in the group of mosaic heterotrimeric G-protein disorders, joining McCune-Albright and Sturge-Weber syndromes. These findings will allow accurate clinical and molecular diagnosis of this subset of common birthmarks, thereby identifying infants at risk for serious complications, and provide novel therapeutic opportunities.

Mots clés

Alleles, Animals, Animals, Genetically Modified, Base Sequence, DNA Mutational Analysis, GTP-Binding Protein alpha Subunits, genetics, GTP-Binding Protein alpha Subunits, Gq-G11, HEK293 Cells, Humans, Infant, Molecular Sequence Data, Mongolian Spot, genetics, Mutation, Mutation, Missense, Neurocutaneous Syndromes, genetics, Phenotype, Phosphorylation, Signal Transduction, Skin Diseases, genetics, Zebrafish


J. Invest. Dermatol.. 2016 Apr;136(4):770-8