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, Harry C Dietz, Lut Van Laer, Bart Loeys

Research output: Contribution to journalArticle

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 languageEnglish (US)
Pages (from-to)621-634
Number of pages14
JournalHuman Mutation
Volume39
Issue number5
DOIs
StatePublished - May 1 2018

Fingerprint

Transforming Growth Factors
Mutation
Genes
Transforming Growth Factor beta3
Uvula
Hypertelorism
Growth Factor Receptors
Aortic Aneurysm
Cleft Palate
Connective Tissue
Databases
Ligands

Keywords

  • aneurysm
  • Loeys–Dietz syndrome
  • SMAD2
  • SMAD3
  • TGFB2
  • TGFB3

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Schepers, D., Tortora, G., Morisaki, H., MacCarrick, G., Lindsay, M., Liang, D., ... 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

A mutation update on the LDS-associated genes TGFB2/3 and SMAD2/3. / Schepers, Dorien; Tortora, Giada; Morisaki, Hiroko; MacCarrick, Gretchen; Lindsay, Mark; Liang, David; Mehta, Sarju G.; Hague, Jennifer; Verhagen, Judith; van de Laar, Ingrid; Wessels, Marja; Detisch, Yvonne; van Haelst, Mieke; Baas, Annette; Lichtenbelt, Klaske; Braun, Kees; van der Linde, Denise; Roos-Hesselink, Jolien; McGillivray, George; Meester, Josephina; Maystadt, Isabelle; Coucke, Paul; El-Khoury, Elie; Parkash, Sandhya; Diness, Birgitte; Risom, Lotte; Scurr, Ingrid; Hilhorst-Hofstee, Yvonne; Morisaki, Takayuki; Richer, Julie; Désir, Julie; Kempers, Marlies; Rideout, Andrea L.; Horne, Gabrielle; Bennett, Chris; Rahikkala, Elisa; Vandeweyer, Geert; Alaerts, Maaike; Verstraeten, Aline; Dietz, Harry C; Van Laer, Lut; Loeys, Bart.

In: Human Mutation, Vol. 39, No. 5, 01.05.2018, p. 621-634.

Research output: Contribution to journalArticle

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, HC, 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
Schepers D, Tortora G, Morisaki H, MacCarrick G, Lindsay M, Liang D et al. A mutation update on the LDS-associated genes TGFB2/3 and SMAD2/3. Human Mutation. 2018 May 1;39(5):621-634. https://doi.org/10.1002/humu.23407
Schepers, Dorien ; Tortora, Giada ; Morisaki, Hiroko ; MacCarrick, Gretchen ; Lindsay, Mark ; Liang, David ; Mehta, Sarju G. ; Hague, Jennifer ; Verhagen, Judith ; van de Laar, Ingrid ; Wessels, Marja ; Detisch, Yvonne ; van Haelst, Mieke ; Baas, Annette ; Lichtenbelt, Klaske ; Braun, Kees ; van der Linde, Denise ; Roos-Hesselink, Jolien ; McGillivray, George ; Meester, Josephina ; Maystadt, Isabelle ; Coucke, Paul ; El-Khoury, Elie ; Parkash, Sandhya ; Diness, Birgitte ; Risom, Lotte ; Scurr, Ingrid ; Hilhorst-Hofstee, Yvonne ; Morisaki, Takayuki ; Richer, Julie ; Désir, Julie ; Kempers, Marlies ; Rideout, Andrea L. ; Horne, Gabrielle ; Bennett, Chris ; Rahikkala, Elisa ; Vandeweyer, Geert ; Alaerts, Maaike ; Verstraeten, Aline ; Dietz, Harry C ; Van Laer, Lut ; Loeys, Bart. / A mutation update on the LDS-associated genes TGFB2/3 and SMAD2/3. In: Human Mutation. 2018 ; Vol. 39, No. 5. pp. 621-634.
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