Somatic GNAQ Mutation is Enriched in Brain Endothelial Cells in Sturge–Weber Syndrome

Huang, Lan; Couto, Javier; Pinto, Anna; Alexandrescu, Sanda; Madsen, Joseph R.; Greene, Arin K.; Şahin, Mustafa; Bischoff, Joyce

doi:10.1016/j.pediatrneurol.2016.10.010

Cited by 59 publications

(60 citation statements)

References 24 publications

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“…It has since been shown that the activating R183Q mutation is enriched in endothelial cells of CM and SWS lesions. 8,9 Different somatic mutations in GNAQ and its homologue GNA11 have been reported in congenital hemangiomas. 10 In contrast, to our knowledge, no somatic variants have been definitely associated with infantile hemangioma.…”

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Association of SomaticGNAQMutation With Capillary Malformations in a Case of Choroidal Hemangioma

et al. 2019

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IMPORTANCE Choroidal hemangiomas are defined by a thickened choroid owing to vessel overgrowth, which may increase the intraocular pressure and lead to glaucoma. Choroidal hemangioma and glaucoma often co-occur in patients with Sturge-Weber syndrome, a rare neurocutaneous disorder characterized by capillary malformations. OBJECTIVE To determine whether the mutation found in most capillary malformations, GNAQ R183Q (c.548G>A), was present in the choroidal hemangioma of a patient with Sturge-Weber syndrome. DESIGN, SETTING, AND PARTICIPANT Using laser-capture microdissection, choroidal blood vessels were isolated from paraffin-embedded tissue sections, and genomic DNA was extracted for mutational analysis. Choroidal sections were analyzed in parallel. A patient with choroidal hemangioma and Sturge-Weber syndrome who had undergone enucleation was analyzed in this study at Boston Children’s Hospital. Negative controls were choroidal tissue from an eye with retinoblastoma and unaffected lung tissue; brain tissue from a different patient with Sturge-Weber syndrome served as a positive control. Infantile hemangioma was analyzed as well. Data were analyzed in 2018. MAIN OUTCOMES AND MEASURES The mutant allelic frequency of GNAQ R183 and GNAQ Q209L/H/P was determined by droplet digital polymerase chain reaction on isolated genomic DNA. The infantile hemangioma marker glucose transporter-1 was visualized by immunofluorescent staining of tissue sections. RESULTS The GNAQ R183Q mutation was present in the patient’s choroidal vessels (21.1%) at a frequency similar to that found in brain tissue from a different patient with Sturge-Weber syndrome (25.1%). In contrast, choroidal vessels from a case of retinoblastoma were negative for the mutation (0.5%), as was lung tissue (0.2%). The patient’s choroidal tissue was negative for the 3 GNAQ mutations associated with congenital hemangioma and for the infantile hemangioma marker glucose transporter-1. CONCLUSIONS AND RELEVANCE The results suggest that a more accurate description for choroidal hemangioma in patients with Sturge-Weber syndrome is choroidal capillary malformation. This finding may explain why propranolol, used to treat infantile hemangiomas, has been largely ineffective in patients with choroidal hemangioma. Further studies are needed to corroborate this finding.

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Association of SomaticGNAQMutation With Capillary Malformations in a Case of Choroidal Hemangioma

et al. 2019

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“…In the ocular, cerebral and facial territories reproducibly affected by Sturge-Weber and cerebrofacial arteriovenous metameric vascular malformation syndromes, there are often malformations of adjacent nerves and NC-derived bones (Krings et al, 2007;Nakashima et al, 2014). Quail-chick xenografts have shown that endothelial cells can differentiate inappropriately in response to signals that are specific to these distinct sectors of NC-derived perivascular or SCP cells (Othman-Hassan et al, 2001); recently, causal somatic mutations in an intracellular signalling effector have been found within endothelial cells of those facial areas affected in Sturge-Weber syndrome (Huang et al, 2017). This implies that there remains a large class of human neurocristopathies to be identified as such, which are not only due to direct or indirect impairment of cell-autonomous NC differentiation, but also to their non-cellautonomous inductive functions.…”

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The diverse neural crest: from embryology to human pathology

2019

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We review here some of the historical highlights in exploratory studies of the vertebrate embryonic structure known as the neural crest. The study of the molecular properties of the cells that it produces, their migratory capacities and plasticity, and the still-growing list of tissues that depend on their presence for form and function, continue to enrich our understanding of congenital malformations, paediatric cancers and evolutionary biology. Developmental biology has been key to our understanding of the neural crest, starting with the early days of experimental embryology and through to today, when increasingly powerful technologies contribute to further insight into this fascinating vertebrate cell population.

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“…[25] Extensive dermal melanocytosis and phakomatosis pigmentovascularis are associated with mutations in GNAQ as well as in GNA11 (which does not have known somatic mutations in patients with SWS). [30] The mutations were detected at very low levels in affected tissues but were undetectable in the blood, indicating that these conditions are post-zygotic mosaic disorders. [28] A more strongly activating mutation in 209L of GNAQ is associated with uveal melanoma.…”

Section: Port-wine Birthmarks and Skin Manifestations In Swsmentioning

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Potential biological targets for bioassay development in drug discovery of Sturge–Weber syndrome

Mohammadipanah

Salimi

2017

Chem Biol Drug Des

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Sturge-Weber Syndrome (SWS) is a neurocutaneous disease with clinical manifestations including ocular (glaucoma), cutaneous (port-wine birthmark), neurologic (seizures), and vascular problems. Molecular mechanisms of SWS pathogenesis are initiated by the somatic mutation in GNAQ. Therefore, no definite treatments exist for SWS and treatment options only mitigate the intensity of its clinical manifestations. Biological assay design for drug discovery against this syndrome demands comprehensive knowledge on mechanisms which are involved in its pathogenesis. By analysis of the interrelated molecular targets of SWS, some in vitro bioassay systems can be allotted for drug screening against its progression. Development of such platforms of bioassay can bring along the implementation of high-throughput screening of natural or synthetic compounds in drug discovery programs. Regarding the fact that study of molecular targets and their integration in biological assay design can facilitate the process of effective drug discovery; some potential biological targets and their respective biological assay for SWS drug discovery are propounded in this review. For this purpose, some biological targets for SWS drug discovery such as acetylcholinesterase, alkaline phosphatase, GABAergic receptors, Hypoxia-Inducible Factor (HIF)-1α and 2α are suggested.

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Somatic GNAQ Mutation is Enriched in Brain Endothelial Cells in Sturge–Weber Syndrome

Cited by 59 publications

References 24 publications

Association of SomaticGNAQMutation With Capillary Malformations in a Case of Choroidal Hemangioma

Association of SomaticGNAQMutation With Capillary Malformations in a Case of Choroidal Hemangioma

The diverse neural crest: from embryology to human pathology

Potential biological targets for bioassay development in drug discovery of Sturge–Weber syndrome

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