PUBLICATION
Mosaic activating mutations in GNA11 and GNAQ are associated with Phakomatosis Pigmentovascularis and Extensive Dermal Melanocytosis
- Authors
- Thomas, A.C., Zeng, Z., Rivière, J.B., O'Shaughnessy, R., Al-Olabi, L., St-Onge, J., Atherton, D.J., Aubert, H., Bagazgoitia, L., Barbarot, S., Bourrat, E., Chiaverini, C., Chong, W.K., Duffourd, Y., Glover, M., Groesser, L., Hadj-Rabia, S., Hamm, H., Happle, R., Mushtaq, I., Lacour, J.P., Waelchli, R., Wobser, M., Vabres, P., Patton, E.E., Kinsler, V.A.
- ID
- ZDB-PUB-160119-5
- Date
- 2016
- Source
- The Journal of investigative dermatology 136(4): 770-8 (Journal)
- Registered Authors
- Patton, E. Elizabeth
- Keywords
- none
- MeSH Terms
-
- 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
- PubMed
- 26778290 Full text @ J. Invest. Dermatol.
Citation
Thomas, A.C., Zeng, Z., Rivière, J.B., O'Shaughnessy, R., Al-Olabi, L., St-Onge, J., Atherton, D.J., Aubert, H., Bagazgoitia, L., Barbarot, S., Bourrat, E., Chiaverini, C., Chong, W.K., Duffourd, Y., Glover, M., Groesser, L., Hadj-Rabia, S., Hamm, H., Happle, R., Mushtaq, I., Lacour, J.P., Waelchli, R., Wobser, M., Vabres, P., Patton, E.E., Kinsler, V.A. (2016) Mosaic activating mutations in GNA11 and GNAQ are associated with Phakomatosis Pigmentovascularis and Extensive Dermal Melanocytosis. The Journal of investigative dermatology. 136(4):770-8.
Abstract
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 can be extensive, permanent and associated with extra-cutaneous abnormalities. Co-occurrence with vascular birthmarks defines a subtype of Phakomatosis Pigmentovascularis (PPV), a group of syndromes associated with neuro-vascular, ophthalmological, overgrowth and malignant complications. Here, we discover that extensive dermal melanocytosis and PPV 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 level in affected tissues but were undetectable in the blood, indicating that these conditions are post-zygotic mosaic disorders. In vitro expression of mutant GNA11(R183C) and GNA11(Q209L) in human cell lines demonstrated activation of the downstream p38 MAPK signalling 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. PPV 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 of serious complications, and will provide novel therapeutic opportunities.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping