TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome.
TGFB2 mutations cause familial thoracic aortic aneurysms and dissections associated with mild systemic features of Marfan syndrome.
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DOI：
10.1038/ng.2348
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发表时间：
2012-07-08
期刊：
影响因子：
30.8
通讯作者：
Milewicz, Dianna M.
中科院分区：
文献类型：
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作者：
Boileau, Catherine;Guo, Dong-Chuan;Hanna, Nadine;Regalado, Ellen S.;Detaint, Delphine;Gong, Limin;Varret, Mathilde;Prakash, Siddharth K.;Li, Alexander H.;d'Indy, Hyacintha;Braverman, Alan C.;Grandchamp, Bernard;Kwartler, Callie S.;Gouya, Laurent;Santos-Cortez, Regie Lyn P.;Abifadel, Marianne;Leal, Suzanne M.;Muti, Christine;Shendure, Jay;Gross, Marie-Sylvie;Rieder, Mark J.;Vahanian, Alec;Nickerson, Deborah A.;Michel, Jean Baptiste;Jondeau, Guillaume;Milewicz, Dianna M.
胸主动脉瘤导致急性主动脉夹层的易感性可以在家族中以常染色体显性方式遗传。对两个无亲缘关系的胸主动脉疾病大家族进行全基因组连锁分析，然后对受影响亲属进行全外显子组测序，确定了TGFB2的致病突变。这些突变，外显子6的移码突变和外显子4的无义突变，与疾病分离，LOD总分为7.7。对来自遗传性胸主动脉疾病家族的276个先证进行Sanger测序，发现另外两个TGFB2突变。TGFB2编码转化生长因子β -2 (TGF-β2)，预计该突变会导致TGFB2单倍功能不全，但矛盾的是，病例的主动脉组织显示TGF-β2表达和免疫染色增加。因此，TGFB2单倍体不足易导致胸主动脉疾病，提示疾病的初始驱动途径是细胞TGF-β2水平下降导致病变主动脉中TGF-β2产生继发性增加。
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 LOD score of 7.7. Sanger sequencing of 276 probands from families with inherited thoracic aortic disease identified two additional TGFB2 mutations. TGFB2 encodes the transforming growth factor beta-2 (TGF-β2) and the mutations are predicted to cause haploinsufficiency for TGFB2, but aortic tissue from cases paradoxically shows increased TGF-β2 expression and immunostaining. Thus, haploinsufficiency of TGFB2 predisposes to thoracic aortic disease, suggesting the initial pathway driving disease is decreased cellular TGF-β2 levels leading to a secondary increase in TGF-β2 production in the diseased aorta.
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影响因子：
10.8
作者：
Inamoto, Sakiko;Kwartler, Callie S.;Milewicz, Dianna M.
通讯作者：
Milewicz, Dianna M.
使用下一代 DNA 测序数据进行变异发现和基因分型的框架。
影响因子：
30.8
作者：
通讯作者：
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影响因子：
9.8
作者：
O'Connell, JR;Weeks, DE
通讯作者：
Weeks, DE
影响因子：
15.9
作者：
Iwata, Jun-ichi;Hacia, Joseph G.;Chai, Yang
通讯作者：
Chai, Yang
影响因子：
5.8
作者：
Lindner, TH;Hoffmann, K
通讯作者：
Hoffmann, K