Nature genetics · 2012
Loss-of-function mutations in TGFB2 cause a syndromic presentation of thoracic aortic aneurysm.
СтатьяПоддержка NIH: внешняя программаПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Lindsay Mark E, Schepers Dorien, Bolar Nikhita Ajit, Doyle Jefferson J, Gallo Elena, Fert-Bober Justyna, Kempers Marlies J E, Fishman Elliot K, Chen Yichun, Myers Loretha, Bjeda Djahita, Oswald Gretchen, Elias Abdallah F, Levy Howard P, Anderlid Britt-Marie, Yang Margaret H, Bongers Ernie M H F, Timmermans Janneke, Braverman Alan C, Canham Natalie, Mortier Geert R, Brunner Han G, Byers Peter H, Van Eyk Jennifer, Van Laer Lut, Dietz Harry C, Loeys Bart L
Аннотация
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.