Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm
Mark E. Lindsay,Dorien Schepers,Nikhita Ajit Bolar,Jefferson J. Doyle,Elena M. Gallo,Justyna Fert-Bober,Marlies Kempers,Elliot K. Fishman,Yichun Chen,Loretha Myers,Djahita Bjeda,Gretchen L. Oswald,Abdallah F. Elias,Howard P. Levy,Britt-Marie Anderlid,Margaret H. Yang,Ernie M.H.F. Bongers,Janneke Timmermans,Alan C. Braverman,Natalie Canham,Geert Mortier,Han G. Brunner,Peter H. Byers,Jennifer E. Van Eyk,Lut Van Laer,Harry C. Dietz,Harry C. Dietz,Bart Loeys +27 more
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TLDR
The hypothesis that compensatory autocrine and/or paracrine events contribute to the pathogenesis of TGF-β–mediated vasculopathies is supported.Abstract:
Loeys-Dietz syndrome (LDS) associates with a tissue signature for high transforming growth factor (TGF)-β signaling but is often caused by heterozygous mutations in genes encoding positive effectors of TGF-β signaling, including either subunit of the TGF-β receptor or SMAD3, thereby engendering controversy regarding the mechanism of disease. Here, we report heterozygous mutations or deletions in the gene encoding the TGF-β2 ligand for a phenotype within the LDS spectrum and show upregulation of TGF-β signaling in aortic tissue from affected individuals. Furthermore, haploinsufficient Tgfb2(+/-) mice have aortic root aneurysm and biochemical evidence of increased canonical and noncanonical TGF-β signaling. Mice that harbor both a mutant Marfan syndrome (MFS) allele (Fbn1(C1039G/+)) and Tgfb2 haploinsufficiency show increased TGF-β signaling and phenotypic worsening in association with normalization of TGF-β2 expression and high expression of TGF-β1. Taken together, these data support the hypothesis that compensatory autocrine and/or paracrine events contribute to the pathogenesis of TGF-β-mediated vasculopathies.read more
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TGF-β and the TGF-β Family: Context-Dependent Roles in Cell and Tissue Physiology
TL;DR: TGF-β is introduced as the best-studied factor among the TGF- β family proteins, with its diversity of roles in the control of cell proliferation and differentiation, wound healing and immune system, and its key roles in pathology, for example, skeletal diseases, fibrosis, and cancer.
Journal ArticleDOI
Clinical development of galunisertib (LY2157299 monohydrate), a small molecule inhibitor of transforming growth factor-beta signaling pathway
Stephan Herbertz,J. Scott Sawyer,Anja Stauber,Ivelina Gueorguieva,Kyla Driscoll,Shawn T. Estrem,Ann Cleverly,Durisala Desaiah,Susan C. Guba,Karim A. Benhadji,Christopher A. Slapak,Michael Lahn +11 more
TL;DR: The use of a pharmacokinetic/pharmacodynamic model defined a therapeutic window with an appropriate safety profile that enabled the clinical investigation of galunisertib, and the past and current experiences with different pharmacological treatments that enabled it to be investigated in patients are summarized.
Journal ArticleDOI
Loeys-Dietz syndrome: a primer for diagnosis and management
Gretchen MacCarrick,James H. Black,Sarah Bowdin,Ismail El-Hamamsy,Pamela A. Frischmeyer-Guerrerio,Anthony L. Guerrerio,Paul D. Sponseller,Bart Loeys,Harry C. Dietz +8 more
TL;DR: This review of literature and expert opinion aims to provide medical guidelines for care of individuals with Loeys–Dietz syndrome.
Journal ArticleDOI
Role of TGF-β Pathway Polymorphisms in Sporadic Thoracic Aortic Aneurysm: rs900 TGF-β2 Is a Marker of Differential Gender Susceptibility
Letizia Scola,Federica Maria Di Maggio,Loredana Vaccarino,M Bova,Giusy I. Forte,Calogera Pisano,Giuseppina Candore,Giuseppina Colonna-Romano,Domenico Lio,Giovanni Ruvolo,Carmela Rita Balistreri +10 more
TL;DR: The most relevant finding obtained allows us to propose that rs900 TGF-β2 SNP is associated with sporadic TAA in women, which might open new perspectives for the analysis of sporadic T AA susceptibility factors and prevention.
Journal ArticleDOI
Mitral valve disease—morphology and mechanisms
Robert A. Levine,Albert Hagège,Daniel P. Judge,Muralidhar Padala,Jacob P. Dal-Bianco,Elena Aikawa,Jonathan Beaudoin,Joyce Bischoff,Nabila Bouatia-Naji,Patrick Bruneval,Jonathan T. Butcher,Alain Carpentier,Miguel Chaput,Adrian H. Chester,Catherine Clusel,Francesca N. Delling,Harry C. Dietz,Christian Dina,Ronen Durst,Leticia Fernández-Friera,Mark D. Handschumacher,Morten O. Jensen,Xavier Jeunemaitre,Hervé Le Marec,Thierry Le Tourneau,Roger R. Markwald,Jean Mérot,Emmanuel Messas,David P. Milan,Tui Neri,Russell A. Norris,David S. Peal,Maelle Perrocheau,Vincent Probst,Michael Pucéat,Nadia Rosenthal,Jorge Solis,Jean-Jacques Schott,Ehud Schwammenthal,Susan A. Slaugenhaupt,Jae-Kwan Song,Magdi H. Yacoub +41 more
TL;DR: The approach, which bridges clinicians and basic scientists, enables the correlation of observed disease with cellular and molecular mechanisms, leading to the discovery of new opportunities for improving the natural history of mitral valve disease.
References
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