GNA14 Somatic Mutation Causes Congenital and Sporadic Vascular Tumors by MAPK Activation

Lim, Young Hee; Bacchiocchi, Antonella; Qiu, Jingyao; Straub, Robert; Bruckner, Anna L.; Bercovitch, Lionel; Narayan, Deepak; McNiff, Jennifer M.; Ko, Christine J.; Robinson‐Bostom, Leslie; Antaya, Richard J.; Halaban, Ruth; Choate, Keith

doi:10.1016/j.ajhg.2016.06.010

Cited by 114 publications

(96 citation statements)

References 44 publications

(51 reference statements)

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“…Consistent with our finding, functional overlap or redundancy between GNAQ and GNA11 also have been observed in uveal melanoma [7], phakomatosis pigmentovascularis [8], melanomas associated with blue nevi [9], and congenital hemangiomas [4]. Although GNA14 shares ~80% amino acid identity with GNAQ and GNA11, and can cause vascular tumors [10], we did not identify GNA14 mutations in capillary malformations.…”

Section: Discussionsupporting

confidence: 89%

A somatic GNA11 mutation is associated with extremity capillary malformation and overgrowth

et al. 2017

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Background Capillary malformation is a cutaneous vascular anomaly that is present at birth, darkens over time, and can cause overgrowth of tissues beneath the stain. The lesion is caused by a somatic activating mutation in GNAQ. In a previous study we were unable to identify a GNAQ mutation in patients with a capillary malformation involving an overgrown lower extremity. We hypothesized that mutations in GNA11 or GNA14, genes closely related to GNAQ, also may cause capillary malformations. Methods Human capillary malformation tissue obtained from 8 patients that had tested negative for GNAQ mutations were studied. Lesions involved an extremity (n=7) or trunk (n=1). Droplet digital PCR (ddPCR) was used to detect GNA11 or GNA14 mutant cells (p.Arg183) in the specimens. Single molecule molecular inversion probe sequencing (smMIP-seq) was performed to search for other mutations in GNA11. Mutations were validated by sublconing and sequencing amplimers. Results We found a somatic GNA11 missense mutation (c.547C>T; p.Arg183Cys) in 3 patients with a diffuse capillary malformation of an extremity. Mutant allelic frequencies ranged from 0.3%–5.0%. GNA11 or GNA14 mutations were not found in 5 affected tissues or in unaffected tissues (white blood cell DNA). Conculsions GNA11 mutations are associated with extremity capillary malformations causing overgrowth. Pharmacotherapy that affects GNA11 signaling may prevent the progression of capillary malformations.

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Section: Discussionsupporting

confidence: 89%

A somatic GNA11 mutation is associated with extremity capillary malformation and overgrowth

et al. 2017

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“…In addition, somatic mutations in GNA14 , another Gαq family member, were recently reported in tufted angiomas, kaposiform hemangioendotheliomas and pyogenic granulomas 24 . In these studies, the cellular residence of the mutations in the vascular tumors was not determined although Lim and colleagues expressed the GNA14 p.Q205L mutation in human umbilical vein endothelial cells.…”

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

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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.

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“…19 Somatic mutations affecting proteins upstream of MEK1 occur in cancer and other types of vascular malformations. 12,19,[29][30][31][32][33][34] The MAP2K1 mutations we detected in AVMs likely alter the function of MEK1 by producing a hypermorphic or neomorphic effect, since these mutations have previously been shown to increase ERK1 and ERK2 phosphorylation in tumors and in cultured cells. Consistent with this hypothesis, mice that are heterozygous for Mek1 knockout alleles do not exhibit a phenotype, whereas homozygous knockout alleles cause embryonic lethality and placental defects.…”

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confidence: 81%

Somatic MAP2K1 Mutations Are Associated with Extracranial Arteriovenous Malformation

Couto

Huang

Konczyk

et al. 2017

The American Journal of Human Genetics

216

168

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Arteriovenous malformation (AVM) is a fast-flow, congenital vascular anomaly that may arise anywhere in the body. AVMs typically progress, causing destruction of surrounding tissue and, sometimes, cardiac overload. AVMs are difficult to control; they often re-expand after embolization or resection, and pharmacologic therapy is unavailable. We studied extracranial AVMs in order to identify their biological basis. We performed whole-exome sequencing (WES) and whole-genome sequencing (WGS) on AVM tissue from affected individuals. Endothelial cells were separated from non-endothelial cells by immune-affinity purification. We used droplet digital PCR (ddPCR) to confirm mutations found by WES and WGS, to determine whether mutant alleles were enriched in endothelial or non-endothelial cells, and to screen additional AVM specimens. In seven of ten specimens, WES and WGS detected and ddPCR confirmed somatic mutations in mitogen activated protein kinase kinase 1 (MAP2K1), the gene that encodes MAP-extracellular signal-regulated kinase 1 (MEK1). Mutant alleles were enriched in endothelial cells and were not present in blood or saliva. 9 of 15 additional AVM specimens contained mutant MAP2K1 alleles. Mutations were missense or small in-frame deletions that affect amino acid residues within or adjacent to the protein's negative regulatory domain. Several of these mutations have been found in cancers and shown to increase MEK1 activity. In summary, somatic mutations in MAP2K1 are a common cause of extracranial AVM. The likely mechanism is endothelial cell dysfunction due to increased MEK1 activity. MEK1 inhibitors, which are approved to treat several forms of cancer, are potential therapeutic agents for individuals with extracranial AVM.Arteriovenous malformation (AVM) is a congenital vascular anomaly, comprised of abnormal connections between arteries and veins that are missing normal high-resistance capillary beds (Figure 1). 1 Sporadic extracranial AVMs are solitary and may be localized or regional. Rapid blood flow is demonstrable by Doppler ultrasonography. Magnetic resonance imaging reveals signal voids consistent with fast-flow, while angiography shows the early filling of draining veins (Figure 1). With time, arterial to venous shunting causes tissue ischemia that leads to pain, ulceration, bleeding, and destruction of adjacent tissues. Treatment for AVM has been discouraging. Embolization and/or resection are often followed by expansion; there are no drug treatments. 2 The purpose of this study was to identify the genetic basis for sporadic, extracranial AVM in an effort to devise a new therapeutic strategy.The Committee on Clinical Investigation at Boston Children's Hospital approved this study and informed consent was obtained from study participants. Ten AVM specimens that had been collected during a clinically indicated procedure, including matched unaffected tissue specimens from three of the study participants, had DNA extracted using the DNeasy Blood & Tissue Kit (QIAGEN); saliva DNA was extracted using the pr...

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GNA14 Somatic Mutation Causes Congenital and Sporadic Vascular Tumors by MAPK Activation

Cited by 114 publications

References 44 publications

A somatic GNA11 mutation is associated with extremity capillary malformation and overgrowth

A somatic GNA11 mutation is associated with extremity capillary malformation and overgrowth

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

Somatic MAP2K1 Mutations Are Associated with Extracranial Arteriovenous Malformation

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