Somatic Activating Mutations in GNAQ and GNA11 Are Associated with Congenital Hemangioma

Ayturk, Ugur M.; Couto, Javier; Hann, Steven; Mulliken, John B.; Williams, Kaitlin; Huang, August Yue; Fishman, Steven J.; Boyd, Theonia K.; Kozakewich, Harry P.; Bischoff, Joyce; Greene, Arin K.; Warman, Matthew L.

doi:10.1016/j.ajhg.2016.05.010

Cited by 55 publications

(37 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mutations in the GNAQ family appear to be common among a variety of sporadic and congenital small vessel lesions . Similar to our findings, mutually exclusive mutations in this family have been identified in congenital haemangiomas and capillary malformations .…”

Section: Clinical and Genetic Features Of Anastomosing Haemangiomassupporting

confidence: 90%

“…All variants were identified at GNAQ codon 209, a known hot‐spot that is commonly mutated in uveal melanoma and blue nevi . Interestingly, somatic mutations in GNAQ and its paralogue GNA11 , members of the alpha q subfamily of G proteins, have been identified recently in various cutaneous haemangiomas, including congenital haemangioma (both rapidly‐involuting congenital haemangioma and non‐involuting congenital haemangioma) and lobular capillary haemangioma . Capillary malformations in Sturge–Weber syndrome and non‐syndromic port‐wine stains also demonstrate somatic GNAQ and GNA11 mutations at R183 .…”

Section: Clinical and Genetic Features Of Anastomosing Haemangiomasmentioning

confidence: 99%

See 1 more Smart Citation

Recurrent GNA14 mutations in anastomosing haemangiomas

et al. 2018

View full text Add to dashboard Cite

Section: Clinical and Genetic Features Of Anastomosing Haemangiomassupporting

confidence: 90%

Section: Clinical and Genetic Features Of Anastomosing Haemangiomasmentioning

confidence: 99%

Recurrent GNA14 mutations in anastomosing haemangiomas

et al. 2018

View full text Add to dashboard Cite

“…Recently, somatic mutations in GNAQ and GNA11 had been identified in congenital hemangioma 23 , indicating GNAQ plays essential roles in vascular growth and vascular development. In addition, somatic mutations in GNA14 , another Gαq family member, were recently reported in tufted angiomas, kaposiform hemangioendotheliomas and pyogenic granulomas 24 .…”

Section: Discussionmentioning

confidence: 99%

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

Huang

Couto

Pinto

et al. 2017

Pediatric Neurology

Self Cite

View full text Add to dashboard Cite

Background Sturge-Weber syndrome (SWS) is a rare congenital neurocutaneous disorder characterized by facial and extracraniofacial capillary malformations and capillary-venule malformations in the leptomeninges. A somatic mosaic mutation in GNAQ (c.548G>A; p.R183Q) was found in SWS brain and skin capillary malformations. Our laboratory showed endothelial cells (ECs) in skin capillary malformations are enriched for the GNAQ mutation. The purpose of this study is to determine whether the GNAQ mutation is also enriched in ECs in affected SWS brain. Methods Two human SWS brain specimens were fractionated by fluorescence-activated cell sorting into hematopoietic (CD45), endothelial (CD31, VE-Cadherin and VEGFR2), perivascular (PDGFRβ) cells and cells negative for all markers. The sorted cell populations were analyzed for GNAQ p.R183Q mutation by droplet digital PCR. SWS patient-derived brain ECs were selected by anti-CD31-coated magnetic beads and cultured in endothelial growth medium in vitro. Results The GNAQ p.R183Q mutation was present in brain ECs in two SWS specimens, with mutant allelic frequencies of 34.7% and 24.0%. Cells negative for all markers also harbored the GNAQ mutation. The mutant allelic frequencies in these unidentified cells were 9.2% and 8.4%. SWS patient-derived brain ECs with mutant allelic frequencies of 14.7% and 21% survived and proliferated in vitro. Conclusions Our study provides evidence that GNAQ p.R183Q mutation is enriched in ECs in SWS brain lesions and thereby reveals ECs as a source of aberrant Gαq signaling. This will help to understand the pathophysiology of SWS, to discover biomarkers for predicting cerebral involvement and to develop therapeutic targets to prevent neurologic impairments in SWS.

show abstract

“…Our identification of GNA14 mutations in KHEs, TAs, and LCHs-three distinct classes of vascular tumors-also highlights the pleiotropy of G aq variants, as seen in GNAQ and GNA11 mutations causing LCHs, PWSs, and NICHs. [10][11][12]16,19 Similarly, activating mutations in HRAS, KRAS, and NRAS also demonstrate phenotypic heterogeneity within vascular anomalies, giving rise to both LCHs and NICHs. 8,9 It remains unclear how identical somatic mutations can give rise to distinct clinical phenotypes.…”

Section: 34mentioning

confidence: 99%

“…8,12,19 A recent survey of 16 congenital hemangiomas identified 12/16 (75%) lesions with GNA11 and GNAQ mutations, but all were Pro or Leu substitutions at Gln209. 10 We further analyzed subjects without a detected mutation. In these subjects, we employed whole-exome sequencing (WES), performed by the Yale Center for Genome Analysis, by using barcoded libraries from sheared genomic DNA (Table S1) (Table S2).…”

mentioning

confidence: 99%

513 GNA14 somatic mutation causes congenital and sporadic vascular tumors by MAPK activation

Lim

Bacchiocchi

Qiu

et al. 2017

Journal of Investigative Dermatology

View full text Add to dashboard Cite

Vascular tumors are among the most common neoplasms in infants and children; 5%-10% of newborns present with or develop lesions within the first 3 months of life. Most are benign infantile hemangiomas that typically regress by 5 years of age; other vascular tumors include congenital tufted angiomas (TAs), kaposiform hemangioendotheliomas (KHEs), and childhood lobular capillary hemangiomas (LCHs). Some of these lesions can become locally invasive and unresponsive to pharmacologic intervention, leading to significant complications. Recent investigation has revealed that activating mutations in HRAS, KRAS, NRAS, GNAQ, and GNA11 can cause certain types of rare childhood vascular tumors, and we have now identified causal recurrent somatic activating mutations in GNA14 by whole-exome and targeted sequencing. We found somatic activating GNA14 c.614A>T (p.Gln205Leu) mutations in one KHE, one TA, and one LCH and a GNA11 c.547C>T (p.Arg183Cys) mutation in two LCH lesions. We examined mutation pathobiology via expression of mutant GNA14 or GNA11 in primary human endothelial cells and melanocytes. GNA14 and GNA11 mutations induced changes in cellular morphology and rendered cells growth-factor independent by upregulating the MAPK pathway. Our findings identify GNA14 mutations as a cause of childhood vascular tumors, offer insight into mechanisms of oncogenic transformation by mutations affecting Gaq family members, and identify potential targets for therapeutic intervention.

show abstract

Somatic Activating Mutations in GNAQ and GNA11 Are Associated with Congenital Hemangioma

Cited by 55 publications

References 0 publications

Recurrent GNA14 mutations in anastomosing haemangiomas

Recurrent GNA14 mutations in anastomosing haemangiomas

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

513 GNA14 somatic mutation causes congenital and sporadic vascular tumors by MAPK activation

Contact Info

Product

Resources

About