期刊
JOURNAL OF INVESTIGATIVE DERMATOLOGY
卷 136, 期 4, 页码 770-778出版社
NATURE PUBLISHING GROUP
DOI: 10.1016/j.jid.2015.11.027
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资金
- Wellcome Trust [WT104076MA]
- National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust
- University College London
- Livingstone Skin Research Centre, UCL Institute of Child Health, London
- Medical Research Council, Human Genetics Unit, Unite Kingdom
- Agence Nationale de la Recherche [ANR-13-PDOC-0029]
- Groupe Interregional de Recherche Clinique et d'Innovation (GIRCI) Est
- Programme Hospitalier de Recherche Clinique (PHRC) National
- MRC [MC_PC_U127585840, MC_U127585840] Funding Source: UKRI
- Medical Research Council [MC_PC_U127585840, MC_U127585840] Funding Source: researchfish
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 Ga 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.
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