TY - JOUR

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

AU - Schepers, Dorien

AU - Tortora, Giada

AU - Morisaki, Hiroko

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

PY - 2018

Y1 - 2018

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

VL - 39

SP - 621

EP - 634

JO - Human Mutation

JF - Human Mutation

SN - 1059-7794

IS - 5

ER -