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

doi:10.1016/j.jid.2016.07.034

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 RieuSamira Syed, Carine van der Vleuten, Rosemarie Watson, Steven J. Fishman, John B. Mulliken, Lauri Eklund, Nisha Limaye, Laurence M. Boon, Miikka Vikkula^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

156 Scopus citations

Abstract

Blue rubber bleb nevus syndrome (Bean syndrome) is a rare, severe disorder of unknown cause, characterized by numerous cutaneous and internal venous malformations; gastrointestinal lesions are pathognomonic. We discovered somatic mutations in TEK, the gene encoding TIE2, in 15 of 17 individuals with blue rubber bleb nevus syndrome. Somatic mutations were also identified in five of six individuals with sporadically occurring multifocal venous malformations. In contrast to common unifocal venous malformation, which is most often caused by the somatic L914F TIE2 mutation, multifocal forms are predominantly caused by double (cis) mutations, that is, two somatic mutations on the same allele of the gene. Mutations are identical in all lesions from a given individual. T1105N-T1106P is recurrent in blue rubber bleb nevus, whereas Y897C-R915C is recurrent in sporadically occurring multifocal venous malformation: both cause ligand-independent activation of TIE2, and increase survival, invasion, and colony formation when expressed in human umbilical vein endothelial cells.

Original language	English (US)
Pages (from-to)	207-216
Number of pages	10
Journal	Journal of Investigative Dermatology
Volume	137
Issue number	1
DOIs	https://doi.org/10.1016/j.jid.2016.07.034
State	Published - Jan 1 2017
Externally published	Yes

ASJC Scopus subject areas

Dermatology
Molecular Biology
Biochemistry
Cell Biology

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10.1016/j.jid.2016.07.034

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Soblet, J., Kangas, J., Nätynki, M., Mendola, A., Helaers, R., Uebelhoer, M., Kaakinen, M., Cordisco, M., Dompmartin, A., Enjolras, O., Holden, S., Irvine, A. D., Kangesu, L., Léauté-Labrèze, C., Lanoel, A., Lokmic, Z., Maas, S., McAleer, M. A., Penington, A., ... Vikkula, M. (2017). Blue Rubber Bleb Nevus (BRBN) Syndrome Is Caused by Somatic TEK (TIE2) Mutations. Journal of Investigative Dermatology, 137(1), 207-216. https://doi.org/10.1016/j.jid.2016.07.034

@article{7ecc9d75014f40a1a03102ed07b78938,

title = "Blue Rubber Bleb Nevus (BRBN) Syndrome Is Caused by Somatic TEK (TIE2) Mutations",

abstract = "Blue rubber bleb nevus syndrome (Bean syndrome) is a rare, severe disorder of unknown cause, characterized by numerous cutaneous and internal venous malformations; gastrointestinal lesions are pathognomonic. We discovered somatic mutations in TEK, the gene encoding TIE2, in 15 of 17 individuals with blue rubber bleb nevus syndrome. Somatic mutations were also identified in five of six individuals with sporadically occurring multifocal venous malformations. In contrast to common unifocal venous malformation, which is most often caused by the somatic L914F TIE2 mutation, multifocal forms are predominantly caused by double (cis) mutations, that is, two somatic mutations on the same allele of the gene. Mutations are identical in all lesions from a given individual. T1105N-T1106P is recurrent in blue rubber bleb nevus, whereas Y897C-R915C is recurrent in sporadically occurring multifocal venous malformation: both cause ligand-independent activation of TIE2, and increase survival, invasion, and colony formation when expressed in human umbilical vein endothelial cells.",

author = "Julie Soblet and Jaakko Kangas and Marjut N{\"a}tynki and Antonella Mendola and Rapha{\"e}l Helaers and Melanie Uebelhoer and Mika Kaakinen and Maria Cordisco and Anne Dompmartin and Odile Enjolras and Simon Holden and Irvine, {Alan D.} and Loshan Kangesu and Christine L{\'e}aut{\'e}-Labr{\`e}ze and Agustina Lanoel and Zerina Lokmic and Saskia Maas and McAleer, {Maeve A.} and Anthony Penington and Paul Rieu and Samira Syed and {van der Vleuten}, Carine and Rosemarie Watson and Fishman, {Steven J.} and Mulliken, {John B.} and Lauri Eklund and Nisha Limaye and Boon, {Laurence M.} and Miikka Vikkula",

note = "Publisher Copyright: {\textcopyright} 2016 The Authors",

year = "2017",

month = jan,

day = "1",

doi = "10.1016/j.jid.2016.07.034",

language = "English (US)",

volume = "137",

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journal = "Journal of Investigative Dermatology",

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Soblet, J, Kangas, J, Nätynki, M, Mendola, A, Helaers, R, Uebelhoer, M, Kaakinen, M, Cordisco, M, Dompmartin, A, Enjolras, O, Holden, S, Irvine, AD, Kangesu, L, Léauté-Labrèze, C, Lanoel, A, Lokmic, Z, Maas, S, McAleer, MA, Penington, A, Rieu, P, Syed, S, van der Vleuten, C, Watson, R, Fishman, SJ, Mulliken, JB, Eklund, L, Limaye, N, Boon, LM & Vikkula, M 2017, 'Blue Rubber Bleb Nevus (BRBN) Syndrome Is Caused by Somatic TEK (TIE2) Mutations', Journal of Investigative Dermatology, vol. 137, no. 1, pp. 207-216. https://doi.org/10.1016/j.jid.2016.07.034

TY - JOUR

T1 - Blue Rubber Bleb Nevus (BRBN) Syndrome Is Caused by Somatic TEK (TIE2) Mutations

AU - Soblet, Julie

AU - Kangas, Jaakko

AU - Nätynki, Marjut

AU - Mendola, Antonella

AU - Helaers, Raphaël

AU - Uebelhoer, Melanie

AU - Kaakinen, Mika

AU - Cordisco, Maria

AU - Dompmartin, Anne

AU - Enjolras, Odile

AU - Holden, Simon

AU - Irvine, Alan D.

AU - Kangesu, Loshan

AU - Léauté-Labrèze, Christine

AU - Lanoel, Agustina

AU - Lokmic, Zerina

AU - Maas, Saskia

AU - McAleer, Maeve A.

AU - Penington, Anthony

AU - Rieu, Paul

AU - Syed, Samira

AU - van der Vleuten, Carine

AU - Watson, Rosemarie

AU - Fishman, Steven J.

AU - Mulliken, John B.

AU - Eklund, Lauri

AU - Limaye, Nisha

AU - Boon, Laurence M.

AU - Vikkula, Miikka

PY - 2017/1/1

Y1 - 2017/1/1

N2 - Blue rubber bleb nevus syndrome (Bean syndrome) is a rare, severe disorder of unknown cause, characterized by numerous cutaneous and internal venous malformations; gastrointestinal lesions are pathognomonic. We discovered somatic mutations in TEK, the gene encoding TIE2, in 15 of 17 individuals with blue rubber bleb nevus syndrome. Somatic mutations were also identified in five of six individuals with sporadically occurring multifocal venous malformations. In contrast to common unifocal venous malformation, which is most often caused by the somatic L914F TIE2 mutation, multifocal forms are predominantly caused by double (cis) mutations, that is, two somatic mutations on the same allele of the gene. Mutations are identical in all lesions from a given individual. T1105N-T1106P is recurrent in blue rubber bleb nevus, whereas Y897C-R915C is recurrent in sporadically occurring multifocal venous malformation: both cause ligand-independent activation of TIE2, and increase survival, invasion, and colony formation when expressed in human umbilical vein endothelial cells.

AB - Blue rubber bleb nevus syndrome (Bean syndrome) is a rare, severe disorder of unknown cause, characterized by numerous cutaneous and internal venous malformations; gastrointestinal lesions are pathognomonic. We discovered somatic mutations in TEK, the gene encoding TIE2, in 15 of 17 individuals with blue rubber bleb nevus syndrome. Somatic mutations were also identified in five of six individuals with sporadically occurring multifocal venous malformations. In contrast to common unifocal venous malformation, which is most often caused by the somatic L914F TIE2 mutation, multifocal forms are predominantly caused by double (cis) mutations, that is, two somatic mutations on the same allele of the gene. Mutations are identical in all lesions from a given individual. T1105N-T1106P is recurrent in blue rubber bleb nevus, whereas Y897C-R915C is recurrent in sporadically occurring multifocal venous malformation: both cause ligand-independent activation of TIE2, and increase survival, invasion, and colony formation when expressed in human umbilical vein endothelial cells.

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DO - 10.1016/j.jid.2016.07.034

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SN - 0022-202X

VL - 137

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JO - Journal of Investigative Dermatology

JF - Journal of Investigative Dermatology

IS - 1

ER -

Blue Rubber Bleb Nevus (BRBN) Syndrome Is Caused by Somatic TEK (TIE2) Mutations

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