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TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome 总被引:1,自引:0,他引:1
C Boileau DC Guo N Hanna ES Regalado D Detaint L Gong M Varret SK Prakash AH Li H d'Indy AC Braverman B Grandchamp CS Kwartler L Gouya RL Santos-Cortez M Abifadel SM Leal C Muti J Shendure MS Gross MJ Rieder A Vahanian DA Nickerson JB Michel;National Heart Lung Blood Institute 《Nature genetics》2012,44(8):916-921
A predisposition for thoracic aortic aneurysms leading to acute aortic dissections can be inherited in families in an autosomal dominant manner. Genome-wide linkage analysis of two large unrelated families with thoracic aortic disease followed by whole-exome sequencing of affected relatives identified causative mutations in TGFB2. These mutations-a frameshift mutation in exon 6 and a nonsense mutation in exon 4-segregated with disease with a combined logarithm of odds (LOD) score of 7.7. Sanger sequencing of 276 probands from families with inherited thoracic aortic disease identified 2 additional TGFB2 mutations. TGFB2 encodes transforming growth factor (TGF)-β2, and the mutations are predicted to cause haploinsufficiency for TGFB2; however, aortic tissue from cases paradoxically shows increased TGF-β2 expression and immunostaining. Thus, haploinsufficiency for TGFB2 predisposes to thoracic aortic disease, suggesting that the initial pathway driving disease is decreased cellular TGF-β2 levels leading to a secondary increase in TGF-β2 production in the diseased aorta. 相似文献
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