1. Blue Rubber Bleb Nevus (BRBN) Syndrome Is Caused by Somatic TEK (TIE2) Mutations 
Julie Soblet, Jaakko Kangas, Marjut Nätynki, Antonella Mendola, Raphaël Helaers, Melanie Uebelhoer, Mika Kaakinen, Maria Cordisco, Anne Dompmartin, Odile Enjolras, Simon Holden, Alan D. Irvine, Loshan Kangesu, Christine Léauté-Labrèze, Agustina Lanoel, Zerina Lokmic, Saskia Maas, Maeve A. McAleer, Anthony Penington, Paul Rieu, Samira Syed, Carine van der Vleuten, Rosemarie Watson, Steven J. Fishman, John B. Mulliken, Lauri Eklund, Nisha Limaye, Laurence M. Boon, Miikka Vikkula 
Journal of Investigative Dermatology 
Volume 137, Issue 1, Pages (January 2017)
DOI: /j.jid
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2. Figure 1
Characteristic clinical features of blue rubber bleb nevus syndrome and sporadically occurring multifocal venous malformation (VM). (a) Multifocal rubbery and hyperkeratotic cutaneous venous malformations on sole (patient #10), (b) intestinal VM, (c) dominant venous malformation on buttock (patient #9), (d) endoscopic image of intestinal venous malformation (patient #9) (Ballieux et al., 2015). (e) Subcutaneous venous malformations on wrist, (f) palm, and (g) tongue (patient #20). (h) Surgical resection of forearm venous malformation (patient #18).
Journal of Investigative Dermatology  , DOI: ( /j.jid )
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3. Figure 2
TIE2 mutations in blue rubber bleb nevus syndrome (BRBN) and sporadically occurring multifocal venous malformation (VM). (a) TIE2 protein variants encoded by the TEK mutations identified in tissues. (b, c) Double (cis) mutations, that is, combinations of two somatic mutations on the same allele identified in (b) BRBN and (c) sporadically occurring multifocal VM. n: number of participants in whom identified; TK: tyrosine kinase domain; KID: kinase insert domain; CT: C-terminal tail. Ligand-independent phosphorylation of double-mutant TIE2 forms (d) T1105N-T1106P, Y897F-R915L and (e) Y897C-R915C. NT, nontransfected control; WT, wild-type TIE2; L914F: common somatic mutant identified in unifocal VM (Limaye et al., 2009). α-pY992: anti-phospho-TIE2 (Tyr 992); α-pY99: anti-pan phospho-Tyr; α-TIE2: anti-TIE2; and αβ-actin: anti-β actin antibodies.
Journal of Investigative Dermatology  , DOI: ( /j.jid )
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4. Figure 3
T1105N-T1106P increases viability and colony formation by spontaneously detached human umbilical vein endothelial cells. (a, top) Compartment invasion, measured by number of green fluorescent protein (GFP) colonies within the nonfluorescent monolayer (red circle; d = days). (a, bottom) Quantification of GFP-cell colonies (25th and 75th percentile, median, average [square], min, max). P < 0.01 overall; *P < 0.05 versus T1105N-T1106P. (b) Cell velocities (5th and 95th percentile, median, average [square], min, max, outliers). NS: nonsignificant, else all significant (P < 0.05). (c, top) Conditioned media (CM) replating assay. Cell colonies (circled) quantified from digitalized images (middle) and compared (means + SD, bottom). P < overall; **P < 0.01, T1105N-T1106P versus NT, WT, R849W, L914F; *P < 0.05, Y897F-R915L versus NT, WT. (d) Proportions of dead versus viable cells in CM; means + SD. ***P < 0.001; **P < 0.01; *P < (e) Number of cells in CM; means + SD. ***P < overall; ***P < 0.01 NT versus rest. NT, nontransfected; WT, wild-type TIE2.
Journal of Investigative Dermatology  , DOI: ( /j.jid )
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5. Figure 4
Spectrum of TEK-mediated venous phenotypes. Schematic representation showing clinical features (top), recurrent mutations (middle), and models of mutation acquisition (bottom). Inherited VMCM and sporadically occurring multifocal VM: multiple variable-sized subcutaneous lesions caused by two temporally separated mutational events in TEK. VMCM: germline R849W (gray) with somatic Y1108* (pink: c.3324T>C, blue: c.3320_3321del); sporadically occurring multifocal VM: earlier mosaic (i.e., detected in blood at low frequency) R915C (gray) with later somatic (i.e., only detected in affected tissue) Y897C (pink). Unifocal VM: single lesion caused by somatic L914F (pink). BRBN: GI lesions, one dominant (sub)cutaneous lesion, several (mainly palmoplantar) small hyperkeratotic cutaneous lesions that increase in size and number with time; caused by T1105N-T1106P (pink), which may be simultaneous or successive somatic events in a common cell-of-origin. BRBN, blue rubber bleb nevus; VM, venous malformation; VMCM, cutaneomucosal venous malformation.
Journal of Investigative Dermatology  , DOI: ( /j.jid )
Copyright © 2016 The Authors Terms and Conditions