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

Abstract

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.

NR4A1 Promotes Diabetic Nephropathy by Activating Mff-Mediated Mitochondrial Fission and Suppressing Parkin-Mediated Mitophagy

“…Consistently with our findings, previous studies have reported that NR4A1 activation was noted in fatty liver disease and atherosclerosis [24,25] and that the genetic deletion of NR4A1 or pharmacological inhibition of NR4A1 retards or prevents the progression of nonalcoholic fatty liver and atherosclerosis [66,67]. Collectively, these observations have demonstrated the sufficiency of NR4A1 to exacerbate chronic metabolic diseases, which may highlight a new method for treating chronic metabolic disorders by targeting NR4A1.…”

GNA11 differentially mediates fibroblast growth factor 2‐ and vascular endothelial growth factor A‐induced cellular responses in human fetoplacental endothelial cells

“…) and GNA11 (Couto et al . ) in mediating angiogenesis. In addition, double knockdown of GNAq and 11 in HUVECs blocks VEGFA‐induced cell migration (Zeng et al .…”

“…More recently, Couto et al . () reported that a somatic mutation of GNA11 is associated with capillary malformation in human. These data suggest the importance of GNA11 with respect to mediating endothelial function, possibly depending on the origins of endothelial cells.…”

Phenotypic association of presence of a somatic GNAQ mutation with port‐wine stain distribution in capillary malformation

“…The present study contains a risk of selection bias since only patients requiring excision were included. Somatic mutations in other genes, such as GNA11 , SMARCA4 , EPHA3 , MYB , PDGFR‐β , PIK3CA , and RASA1 , have been found in patients with capillary malformation; however mutations of those genes were not evaluated in this study Genetic assays for those genes might provide a clearer perspective on the genotype‐phenotype associations in capillary malformation and Sturge‐Weber syndrome.…”