title: Mosaic Activating Mutations in GNA11 and GNAQ Are Associated with Phakomatosis Pigmentovascularis and Extensive Dermal Melanocytosis.
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 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.
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, London, UK.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Thomas
authors.affiliation: MRC Institute of Genetics and Molecular Medicine, MRC Human Genetics Unit & Edinburgh Cancer Research UK Centre, Edinburgh, UK.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Zeng
authors.affiliation: Equipe d'Accueil 4271, Génétique des Anomalies du Développement, University of Burgundy, Dijon, France.
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Rivière
authors.affiliation: Livingstone Skin Research Unit, UCL Institute of Child Health, London, UK.
authors.forename: Ryan
authors.initials: R
authors.lastname: O'Shaughnessy
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, London, UK.
authors.forename: Lara
authors.initials: L
authors.lastname: Al-Olabi
authors.affiliation: Equipe d'Accueil 4271, Génétique des Anomalies du Développement, University of Burgundy, Dijon, France.
authors.forename: Judith
authors.initials: J
authors.lastname: St-Onge
authors.affiliation: Paediatric Dermatology, Great Ormond Street Hospital for Children, London, UK.
authors.forename: David J
authors.initials: DJ
authors.lastname: Atherton
authors.affiliation: Department of Dermatology, Nantes University Hospital, Nantes, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Aubert
authors.affiliation: Dermatology, Hospital Universitario Ramón y Cajal, Madrid, Spain.
authors.forename: Lorea
authors.initials: L
authors.lastname: Bagazgoitia
authors.affiliation: Department of Dermatology, Nantes University Hospital, Nantes, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Barbarot
authors.affiliation: Dermatology, Saint-Louis Hospital, Paris, France; General Paediatrics, Robert-Debré Hospital, Paris, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Bourrat
authors.affiliation: Dermatology, University Hospital of Nice, Nice, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Chiaverini
authors.affiliation: Neuroradiology, Great Ormond Street Hospital for Children, London, UK.
authors.forename: W Kling
authors.initials: WK
authors.lastname: Chong
authors.affiliation: Equipe d'Accueil 4271, Génétique des Anomalies du Développement, University of Burgundy, Dijon, France.
authors.forename: Yannis
authors.initials: Y
authors.lastname: Duffourd
authors.affiliation: Paediatric Dermatology, Great Ormond Street Hospital for Children, London, UK.
authors.forename: Mary
authors.initials: M
authors.lastname: Glover
authors.affiliation: Dermatology, Regensburg University Clinic, Regensburg, Germany.
authors.forename: Leopold
authors.initials: L
authors.lastname: Groesser
authors.affiliation: Paediatric Dermatology, Necker Enfants-Malades Hospital, Paris, France.
authors.forename: Smail
authors.initials: S
authors.lastname: Hadj-Rabia
authors.affiliation: Dermatology, University Hospital Wuerzburg, Wuerzburg, Germany.
authors.forename: Henning
authors.initials: H
authors.lastname: Hamm
authors.affiliation: Dermatology, Freiburg University Medical Center, University of Freiburg, Freiburg, Germany.
authors.forename: Rudolf
authors.initials: R
authors.lastname: Happle
authors.affiliation: Paediatric Urology, Great Ormond Street Hospital for Children, London, UK.
authors.forename: Imran
authors.initials: I
authors.lastname: Mushtaq
authors.affiliation: Dermatology, University Hospital of Nice, Nice, France.
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Lacour
authors.affiliation: Paediatric Dermatology, Great Ormond Street Hospital for Children, London, UK.
authors.forename: Regula
authors.initials: R
authors.lastname: Waelchli
authors.affiliation: Dermatology, University Hospital Wuerzburg, Wuerzburg, Germany.
authors.forename: Marion
authors.initials: M
authors.lastname: Wobser
authors.affiliation: Equipe d'Accueil 4271, Génétique des Anomalies du Développement, University of Burgundy, Dijon, France; Dermatology, Dijon University Hospital, Dijon, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Vabres
authors.affiliation: MRC Institute of Genetics and Molecular Medicine, MRC Human Genetics Unit & Edinburgh Cancer Research UK Centre, Edinburgh, UK. Electronic address: e.patton@igmm.ed.ac.uk.
authors.forename: E Elizabeth
authors.initials: EE
authors.lastname: Patton
authors.affiliation: Genetics and Genomic Medicine, UCL Institute of Child Health, London, UK; Paediatric Dermatology, Great Ormond Street Hospital for Children, London, UK. Electronic address: v.kinsler@ucl.ac.uk.
authors.forename: Veronica A
authors.initials: VA
authors.lastname: Kinsler
mesh_terms: D000483:Alleles; D000818:Animals; D030801:Animals, Genetically Modified; D001483:Base Sequence; D004252:DNA Mutational Analysis; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D057809:HEK293 Cells; D006801:Humans; D007223:Infant; D008969:Molecular Sequence Data; D049328:Mongolian Spot / Q000235:genetics*; D009154:Mutation; D020125:Mutation, Missense; D020752:Neurocutaneous Syndromes / Q000235:genetics*; D010641:Phenotype; D010766:Phosphorylation; D015398:Signal Transduction; D012871:Skin Diseases / Q000235:genetics*; D015027:Zebrafish
chemical_list: C554062:GNA11 protein, human; C554061:GNAQ protein, human; D044385:GTP-Binding Protein alpha Subunits; D043802:GTP-Binding Protein alpha Subunits, Gq-G11