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 subcloning 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 to 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.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Shirley MD, Tang H, Gallione CJ et al (2013) Sturge–Weber syndrome and port-wine stains caused by somatic mutation in GNAQ. N Engl J Med 368:1971–1979
Nakashima M, Miyajima M, Sugano H et al (2014) The somatic GNAQ mutation c.548G > A (p. R183Q) is consistently found in Sturge–Weber syndrome. J Hum Genet 59:691–693
Couto JA, Huang L, Vivero MP et al (2016) Endothelial cells from capillary malformations are enriched for Somatic GNAQ mutations. Plast Reconstr Surg 137:77e–82e
Ayturk UM, Couto JA, Hann S et al (2016) Somatic activating mutations in GNAQ and GNA11 are associated with congenital hemangioma. Am J Hum Genet 98:789–795
Lee MS, Liang MG, Mulliken JB (2013) Diffuse capillary malformation with overgrowth: a clinical subtype of vascular anomalies with hypertrophy. J Am Acad Dermatol 69:589–594
Lian CG, Sholl LM, Zakka LR et al (2014) Novel genetic mutations in a sporadic port-wine stain. JAMA Dermatol 150:1336–1340
Metz CH, Scheulen M, Bornfeld N, Lohmann D, Zeschnigk M (2013) Ultradeep sequencing detects GNAQ and GNA11 mutations in cell-free DNA from plasma of patients with uveal melanoma. Cancer Med 2:208–215
Thomas AC, Zeng Z, Riviere JB et al (2016) Mosaic activating mutations in GNA11 and GNAQ Are Associated with Phakomatosis Pigmentovascularis and Extensive Dermal Melanocytosis. J Invest Dermatol 136:770–778
Costa S, Byrne M, Pissaloux D et al (2016) Melanomas associated with blue nevi or mimicking cellular blue nevi: clinical, pathologic, and molecular study of 11 cases displaying a high frequency of GNA11 mutations, BAP1 expression loss, and a predilection for the scalp. Am J Surg Pathol 40:368–377
Lim YH, Bacchiocchi A, Qiu J et al (2016) GNA14 somatic mutation causes congenital and sporadic vascular tumors by MAPK activation. Am J Hum Genet 99:443–450
Van Raamsdonk CD, Griewank KG, Crosby MB et al (2010) Mutations in GNA11 in uveal melanoma. N Engl J Med 363:2191–2199
Sivaraj KK, Li R, Albarran-Juarez J et al (2015) Endothelial Galphaq/11 is required for VEGF-induced vascular permeability and angiogenesis. Cardiovasc Res 108:171–180
Zeng H, Zhao D, Mukhopadhyay D (2002) KDR stimulates endothelial cell migration through heterotrimeric G protein Gq/11-mediated activation of a small GTPase RhoA. J Biol Chem 277:46791–46798
Zeng H, Zhao D, Yang S, Datta K, Mukhopadhyay D (2003) Heterotrimeric G alpha q/G alpha 11 proteins function upstream of vascular endothelial growth factor (VEGF) receptor-2 (KDR) phosphorylation in vascular permeability factor/VEGF signaling. J Biol Chem 278:20738–20745
Acknowledgements
Research reported in this manuscript was supported by the National Institutes of Health Award NICHD-81004 (AKG), National Institutes of Health Award NICHD-82606 (AKG), National Institutes of Health Award HL12703 (JB, AKG), National Institutes of Health Award AR-64231 (MLW), the Translational Research Program Mid-Career Award Boston Children’s Hospital (AKG), and the Translational Neuroscience Center Pilot Study Award Boston Children’s Hospital (JB, AKG). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors have no disclosures.
Rights and permissions
About this article
Cite this article
Couto, J.A., Ayturk, U.M., Konczyk, D.J. et al. A somatic GNA11 mutation is associated with extremity capillary malformation and overgrowth. Angiogenesis 20, 303–306 (2017). https://doi.org/10.1007/s10456-016-9538-1
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10456-016-9538-1