A mutation update on the LDS-associated genes TGFB2/3 and SMAD2/3

Dorien Schepers; Giada Tortora; Hiroko Morisaki; Gretchen MacCarrick; Mark Lindsay; David Liang; Sarju G. Mehta; Jennifer Hague; Judith Verhagen; Ingrid van de Laar; Marja Wessels; Yvonne Detisch; Mieke van Haelst; Annette Baas; Klaske Lichtenbelt; Kees Braun; Denise van der Linde; Jolien Roos-Hesselink; George McGillivray; Josephina Meester; Isabelle Maystadt; Paul Coucke; Elie El-Khoury; Sandhya Parkash; Birgitte Diness; Lotte Risom; Ingrid Scurr; Yvonne Hilhorst-Hofstee; Takayuki Morisaki; Julie Richer; Julie Désir; Marlies Kempers; Andrea L. Rideout; Gabrielle Horne; Chris Bennett; Elisa Rahikkala; Geert Vandeweyer; Maaike Alaerts; Aline Verstraeten; Hal Dietz; Lut Van Laer; Bart Loeys

doi:10.1002/humu.23407

A mutation update on the LDS-associated genes TGFB2/3 and SMAD2/3

Dorien Schepers, Giada Tortora, Hiroko Morisaki, Gretchen MacCarrick, Mark Lindsay, David Liang, Sarju G. Mehta, Jennifer Hague, Judith Verhagen, Ingrid van de Laar, Marja Wessels, Yvonne Detisch, Mieke van Haelst, Annette Baas, Klaske Lichtenbelt, Kees Braun, Denise van der Linde, Jolien Roos-Hesselink, George McGillivray, Josephina MeesterIsabelle Maystadt, Paul Coucke, Elie El-Khoury, Sandhya Parkash, Birgitte Diness, Lotte Risom, Ingrid Scurr, Yvonne Hilhorst-Hofstee, Takayuki Morisaki, Julie Richer, Julie Désir, Marlies Kempers, Andrea L. Rideout, Gabrielle Horne, Chris Bennett, Elisa Rahikkala, Geert Vandeweyer, Maaike Alaerts, Aline Verstraeten, Hal Dietz, Lut Van Laer, Bart Loeys^*

^*Corresponding author for this work

Department of Clinical Medicine

49 Citations (Scopus)

28 Downloads (Pure)

Abstract

The Loeys–Dietz syndrome (LDS) is a connective tissue disorder affecting the cardiovascular, skeletal, and ocular system. Most typically, LDS patients present with aortic aneurysms and arterial tortuosity, hypertelorism, and bifid/broad uvula or cleft palate. Initially, mutations in transforming growth factor-β (TGF-β) receptors (TGFBR1 and TGFBR2) were described to cause LDS, hereby leading to impaired TGF-β signaling. More recently, TGF-β ligands, TGFB2 and TGFB3, as well as intracellular downstream effectors of the TGF-β pathway, SMAD2 and SMAD3, were shown to be involved in LDS. This emphasizes the role of disturbed TGF-β signaling in LDS pathogenesis. Since most literature so far has focused on TGFBR1/2, we provide a comprehensive review on the known and some novel TGFB2/3 and SMAD2/3 mutations. For TGFB2 and SMAD3, the clinical manifestations, both of the patients previously described in the literature and our newly reported patients, are summarized in detail. This clearly indicates that LDS concerns a disorder with a broad phenotypical spectrum that is still emerging as more patients will be identified. All mutations described here are present in the corresponding Leiden Open Variant Database.

Original language	English
Journal	Human Mutation
Volume	39
Issue number	5
Pages (from-to)	621-634
Number of pages	14
ISSN	1059-7794
DOIs	https://doi.org/10.1002/humu.23407
Publication status	Published - 2018

Keywords

aneurysm
Loeys–Dietz syndrome
SMAD2
SMAD3
TGFB2
TGFB3

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A mutation update on the LDS‐associated genes TGFB2/3 and SMAD2/3Final published version, 777 KBLicence: CC BY

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Schepers, D., Tortora, G., Morisaki, H., MacCarrick, G., Lindsay, M., Liang, D., Mehta, S. G., Hague, J., Verhagen, J., van de Laar, I., Wessels, M., Detisch, Y., van Haelst, M., Baas, A., Lichtenbelt, K., Braun, K., van der Linde, D., Roos-Hesselink, J., McGillivray, G., ... Loeys, B. (2018). A mutation update on the LDS-associated genes TGFB2/3 and SMAD2/3. Human Mutation, 39(5), 621-634. https://doi.org/10.1002/humu.23407

Schepers, D, Tortora, G, Morisaki, H, MacCarrick, G, Lindsay, M, Liang, D, Mehta, SG, Hague, J, Verhagen, J, van de Laar, I, Wessels, M, Detisch, Y, van Haelst, M, Baas, A, Lichtenbelt, K, Braun, K, van der Linde, D, Roos-Hesselink, J, McGillivray, G, Meester, J, Maystadt, I, Coucke, P, El-Khoury, E, Parkash, S, Diness, B, Risom, L, Scurr, I, Hilhorst-Hofstee, Y, Morisaki, T, Richer, J, Désir, J, Kempers, M, Rideout, AL, Horne, G, Bennett, C, Rahikkala, E, Vandeweyer, G, Alaerts, M, Verstraeten, A, Dietz, H, Van Laer, L & Loeys, B 2018, 'A mutation update on the LDS-associated genes TGFB2/3 and SMAD2/3', Human Mutation, vol. 39, no. 5, pp. 621-634. https://doi.org/10.1002/humu.23407

@article{eea275f0092b44318b94cc11867d6b62,

title = "A mutation update on the LDS-associated genes TGFB2/3 and SMAD2/3",

abstract = "The Loeys–Dietz syndrome (LDS) is a connective tissue disorder affecting the cardiovascular, skeletal, and ocular system. Most typically, LDS patients present with aortic aneurysms and arterial tortuosity, hypertelorism, and bifid/broad uvula or cleft palate. Initially, mutations in transforming growth factor-β (TGF-β) receptors (TGFBR1 and TGFBR2) were described to cause LDS, hereby leading to impaired TGF-β signaling. More recently, TGF-β ligands, TGFB2 and TGFB3, as well as intracellular downstream effectors of the TGF-β pathway, SMAD2 and SMAD3, were shown to be involved in LDS. This emphasizes the role of disturbed TGF-β signaling in LDS pathogenesis. Since most literature so far has focused on TGFBR1/2, we provide a comprehensive review on the known and some novel TGFB2/3 and SMAD2/3 mutations. For TGFB2 and SMAD3, the clinical manifestations, both of the patients previously described in the literature and our newly reported patients, are summarized in detail. This clearly indicates that LDS concerns a disorder with a broad phenotypical spectrum that is still emerging as more patients will be identified. All mutations described here are present in the corresponding Leiden Open Variant Database.",

keywords = "aneurysm, Loeys–Dietz syndrome, SMAD2, SMAD3, TGFB2, TGFB3",

author = "Dorien Schepers and Giada Tortora and Hiroko Morisaki and Gretchen MacCarrick and Mark Lindsay and David Liang and Mehta, {Sarju G.} and Jennifer Hague and Judith Verhagen and {van de Laar}, Ingrid and Marja Wessels and Yvonne Detisch and {van Haelst}, Mieke and Annette Baas and Klaske Lichtenbelt and Kees Braun and {van der Linde}, Denise and Jolien Roos-Hesselink and George McGillivray and Josephina Meester and Isabelle Maystadt and Paul Coucke and Elie El-Khoury and Sandhya Parkash and Birgitte Diness and Lotte Risom and Ingrid Scurr and Yvonne Hilhorst-Hofstee and Takayuki Morisaki and Julie Richer and Julie D{\'e}sir and Marlies Kempers and Rideout, {Andrea L.} and Gabrielle Horne and Chris Bennett and Elisa Rahikkala and Geert Vandeweyer and Maaike Alaerts and Aline Verstraeten and Hal Dietz and {Van Laer}, Lut and Bart Loeys",

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T1 - A mutation update on the LDS-associated genes TGFB2/3 and SMAD2/3

AU - Schepers, Dorien

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AU - MacCarrick, Gretchen

AU - Lindsay, Mark

AU - Liang, David

AU - Mehta, Sarju G.

AU - Hague, Jennifer

AU - Verhagen, Judith

AU - van de Laar, Ingrid

AU - Wessels, Marja

AU - Detisch, Yvonne

AU - van Haelst, Mieke

AU - Baas, Annette

AU - Lichtenbelt, Klaske

AU - Braun, Kees

AU - van der Linde, Denise

AU - Roos-Hesselink, Jolien

AU - McGillivray, George

AU - Meester, Josephina

AU - Maystadt, Isabelle

AU - Coucke, Paul

AU - El-Khoury, Elie

AU - Parkash, Sandhya

AU - Diness, Birgitte

AU - Risom, Lotte

AU - Scurr, Ingrid

AU - Hilhorst-Hofstee, Yvonne

AU - Morisaki, Takayuki

AU - Richer, Julie

AU - Désir, Julie

AU - Kempers, Marlies

AU - Rideout, Andrea L.

AU - Horne, Gabrielle

AU - Bennett, Chris

AU - Rahikkala, Elisa

AU - Vandeweyer, Geert

AU - Alaerts, Maaike

AU - Verstraeten, Aline

AU - Dietz, Hal

AU - Van Laer, Lut

AU - Loeys, Bart

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N2 - The Loeys–Dietz syndrome (LDS) is a connective tissue disorder affecting the cardiovascular, skeletal, and ocular system. Most typically, LDS patients present with aortic aneurysms and arterial tortuosity, hypertelorism, and bifid/broad uvula or cleft palate. Initially, mutations in transforming growth factor-β (TGF-β) receptors (TGFBR1 and TGFBR2) were described to cause LDS, hereby leading to impaired TGF-β signaling. More recently, TGF-β ligands, TGFB2 and TGFB3, as well as intracellular downstream effectors of the TGF-β pathway, SMAD2 and SMAD3, were shown to be involved in LDS. This emphasizes the role of disturbed TGF-β signaling in LDS pathogenesis. Since most literature so far has focused on TGFBR1/2, we provide a comprehensive review on the known and some novel TGFB2/3 and SMAD2/3 mutations. For TGFB2 and SMAD3, the clinical manifestations, both of the patients previously described in the literature and our newly reported patients, are summarized in detail. This clearly indicates that LDS concerns a disorder with a broad phenotypical spectrum that is still emerging as more patients will be identified. All mutations described here are present in the corresponding Leiden Open Variant Database.

AB - The Loeys–Dietz syndrome (LDS) is a connective tissue disorder affecting the cardiovascular, skeletal, and ocular system. Most typically, LDS patients present with aortic aneurysms and arterial tortuosity, hypertelorism, and bifid/broad uvula or cleft palate. Initially, mutations in transforming growth factor-β (TGF-β) receptors (TGFBR1 and TGFBR2) were described to cause LDS, hereby leading to impaired TGF-β signaling. More recently, TGF-β ligands, TGFB2 and TGFB3, as well as intracellular downstream effectors of the TGF-β pathway, SMAD2 and SMAD3, were shown to be involved in LDS. This emphasizes the role of disturbed TGF-β signaling in LDS pathogenesis. Since most literature so far has focused on TGFBR1/2, we provide a comprehensive review on the known and some novel TGFB2/3 and SMAD2/3 mutations. For TGFB2 and SMAD3, the clinical manifestations, both of the patients previously described in the literature and our newly reported patients, are summarized in detail. This clearly indicates that LDS concerns a disorder with a broad phenotypical spectrum that is still emerging as more patients will be identified. All mutations described here are present in the corresponding Leiden Open Variant Database.

KW - aneurysm

KW - Loeys–Dietz syndrome

KW - SMAD2

KW - SMAD3

KW - TGFB2

KW - TGFB3

U2 - 10.1002/humu.23407

DO - 10.1002/humu.23407

M3 - Journal article

C2 - 29392890

AN - SCOPUS:85043291458

SN - 1059-7794

VL - 39

SP - 621

EP - 634

JO - Human Mutation

JF - Human Mutation

IS - 5

ER -

A mutation update on the LDS-associated genes TGFB2/3 and SMAD2/3

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Keywords

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