A novel somatic mutation in GNAQ in a capillary malformation provides insight into molecular pathogenesis

Galeffi, Francesca; Snellings, Daniel A.; Wetzel-Strong, Sarah E.; Kastelic, Nicolai; Gallione, Carol J.; North, Paula E.; Marchuk, Douglas A.

doi:10.1007/s10456-022-09841-w

Cited by 13 publications

(22 citation statements)

References 30 publications

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“…Quantification for EdU + /CD31 + events showed a significant (p < 0.0001) decrease in the number of EdU + EC in the intestinal muscularis (Fig. 7g, h and Supplementary Movies 11,12) and in the subcutaneous tissue of Trametinib-treated iCdh5-GNAQ Q209L mice compared to vehicle-treated (Supplementary Fig. 15).…”

Section: Increased Endothelial Mapk/erk Signaling In Murine and Patie...mentioning

confidence: 95%

“…Studies in uveal melanoma have shown that this leads to hyperactivation of downstream effector molecules such as protein kinase C (PKC) and the mitogen-activated protein kinase (MAPK) cascade, which can lead to increased cellular proliferation 11 . To date, the EC-specific molecular and signaling consequences of hyperactive GNAQ are not well-defined, except for a handful of in vitro studies suggesting increased MAPK/ ERK activity 2,4,12 . Furthermore, despite these genetic and mechanistic findings, genetic murine models for GNAQ-related vascular anomalies have not yet been reported.…”

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confidence: 99%

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MEK inhibition reduced vascular tumor growth and coagulopathy in a mouse model with hyperactive GNAQ

et al. 2023

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Activating non-inherited mutations in the guanine nucleotide-binding protein G(q) subunit alpha (GNAQ) gene family have been identified in childhood vascular tumors. Patients experience extensive disfigurement, chronic pain and severe complications including a potentially lethal coagulopathy termed Kasabach-Merritt phenomenon. Animal models for this class of vascular tumors do not exist. This has severely hindered the discovery of the molecular consequences of GNAQ mutations in the vasculature and, in turn, the preclinical development of effective targeted therapies. Here we report a mouse model expressing hyperactive mutant GNAQ in endothelial cells. Mutant mice develop vascular and coagulopathy phenotypes similar to those seen in patients. Mechanistically, by transcriptomic analysis we demonstrate increased mitogen activated protein kinase signaling in the mutant endothelial cells. Targeting of this pathway with Trametinib suppresses the tumor growth by reducing vascular cell proliferation and permeability. Trametinib also prevents the development of coagulopathy and improves mouse survival.

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Section: Increased Endothelial Mapk/erk Signaling In Murine and Patie...mentioning

confidence: 95%

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confidence: 99%

MEK inhibition reduced vascular tumor growth and coagulopathy in a mouse model with hyperactive GNAQ

et al. 2023

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“…Interestingly, GNAQ mutations drive constitutively active PLCB3 which increases ANGPT2—as a corollary, blocking ANGPT2 normalized enlarged vessels suggesting a potential treatment approach for Sturge-Weber syndrome [ 261 ]. Recently, a new mutation (Q209R) was identified in a Sturge-Weber syndrome patient; ectopic generation of the Q209R mutation in cultured ECs was sufficient to cause blood vessel (dys)morphogenesis [ 262 ].…”

Section: Angiogenesis and Anti-angiogenesis In Diseasesmentioning

confidence: 99%

Pathological angiogenesis: mechanisms and therapeutic strategies

Dudley

2023

Angiogenesis

112

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In multicellular organisms, angiogenesis, the formation of new blood vessels from pre-existing ones, is an essential process for growth and development. Different mechanisms such as vasculogenesis, sprouting, intussusceptive, and coalescent angiogenesis, as well as vessel co-option, vasculogenic mimicry and lymphangiogenesis, underlie the formation of new vasculature. In many pathological conditions, such as cancer, atherosclerosis, arthritis, psoriasis, endometriosis, obesity and SARS-CoV-2(COVID-19), developmental angiogenic processes are recapitulated, but are often done so without the normal feedback mechanisms that regulate the ordinary spatial and temporal patterns of blood vessel formation. Thus, pathological angiogenesis presents new challenges yet new opportunities for the design of vascular-directed therapies. Here, we provide an overview of recent insights into blood vessel development and highlight novel therapeutic strategies that promote or inhibit the process of angiogenesis to stabilize, reverse, or even halt disease progression. In our review, we will also explore several additional aspects (the angiogenic switch, hypoxia, angiocrine signals, endothelial plasticity, vessel normalization, and endothelial cell anergy) that operate in parallel to canonical angiogenesis mechanisms and speculate how these processes may also be targeted with anti-angiogenic or vascular-directed therapies.

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“…CMs are usually sporadic and appear as flat, red to purple lesions named port-wine stain (nevus flammeus). The etiology of CMs is represented by ASM in the GNAQ gene, located on chromosome 9q21.2 [ 6 , 14 , 15 ].…”

Section: Vascular Anomalies: Ras/raf/mapk/erk Signaling Pathways (Ras...mentioning

confidence: 99%

“…However, the effect of GNAQ p.Arg183Gln in MAPK signal transduction appears to be weaker in terms of activation of downstream effectors than the effect of the more frequently detected GNAQ p.Gln209Leu substitution in uveal melanoma tissue [ 14 ]. Galeffi et al [ 15 ] identified the presence of the GNAQ p.R183Q mutation in most of the patients with SWS that were analyzed, and in one patient, a new GNAQ Q209R mutation was identified [ 15 ].…”

Section: Vascular Anomalies: Ras/raf/mapk/erk Signaling Pathways (Ras...mentioning

confidence: 99%

The Genetic Architecture of Vascular Anomalies: Current Data and Future Therapeutic Perspectives Correlated with Molecular Mechanisms

Butnariu

Gorduza

Florea

et al. 2022

IJMS

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Vascular anomalies (VAs) are morphogenesis defects of the vascular system (arteries, capillaries, veins, lymphatic vessels) singularly or in complex combinations, sometimes with a severe impact on the quality of life. The progress made in recent years with the identification of the key molecular pathways (PI3K/AKT/mTOR and RAS/BRAF/MAPK/ERK) and the gene mutations that lead to the appearance of VAs has allowed the deciphering of their complex genetic architecture. Understanding these mechanisms is critical both for the correct definition of the phenotype and classification of VAs, as well as for the initiation of an optimal therapy and the development of new targeted therapies. The purpose of this review is to present in synthesis the current data related to the genetic factors involved in the etiology of VAs, as well as the possible directions for future research. We analyzed the data from the literature related to VAs, using databases (Google Scholar, PubMed, MEDLINE, OMIM, MedGen, Orphanet) and ClinicalTrials.gov. The obtained results revealed that the phenotypic variability of VAs is correlated with genetic heterogeneity. The identification of new genetic factors and the molecular mechanisms in which they intervene, will allow the development of modern therapies that act targeted as a personalized therapy. We emphasize the importance of the geneticist in the diagnosis and treatment of VAs, as part of a multidisciplinary team involved in the management of VAs.

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A novel somatic mutation in GNAQ in a capillary malformation provides insight into molecular pathogenesis

Cited by 13 publications

References 30 publications

MEK inhibition reduced vascular tumor growth and coagulopathy in a mouse model with hyperactive GNAQ

MEK inhibition reduced vascular tumor growth and coagulopathy in a mouse model with hyperactive GNAQ

Pathological angiogenesis: mechanisms and therapeutic strategies

The Genetic Architecture of Vascular Anomalies: Current Data and Future Therapeutic Perspectives Correlated with Molecular Mechanisms

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