Pleiotropic role of TRAF7 in skull-base meningiomas and congenital heart disease.
Pleiotropic role of TRAF7 in skull-base meningiomas and congenital heart disease.
复制标题
DOI：
10.1073/pnas.2214997120
复制
发表时间：
2023-04-18
影响因子：
11.1
通讯作者：
Gunel, Murat
中科院分区：
文献类型：
--
作者：
Mishra-Gorur, Ketu;Barak, Tanyeri;Kaulen, Leon D.;Henegariu, Octavian;Jin, Sheng Chih;Aguilera, Stephanie Marie;Yalbir, Ezgi;Goles, Gizem;Nishimura, Sayoko;Miyagishima, Danielle;Djenoune, Lydia;Altinok, Selin;Rai, Devendra K.;Viviano, Stephen;Prendergast, Andrew;Zerillo, Cynthia;Ozcan, Kent;Baran, Burcin;Sencar, Leman;Goc, Nukte;Yarman, Yanki;Ercan-Sencicek, A. Gulhan;Bilguvar, Kaya;Lifton, Richard P.;Moliterno, Jennifer;Louvi, Angeliki;Yuan, Shiaulou;Deniz, Engin;Brueckner, Martina;Gunel, Murat
先天性心脏病（CHD）癌症风险增加的遗传基础在很大程度上尚不清楚。我们的研究是重要的，因为它确定了TRAF 7（肿瘤坏死因子受体相关因子7）突变，脑肿瘤（脑膜瘤）和CHD。虽然TRAF 7的体细胞突变是前颅底脑膜瘤的基础，但在这里我们报告了导致CHD的TRAF 7遗传突变，并表明两种不同病理的共同遗传学可以追溯到神经嵴两种组织的共同发育起源。我们证明，这些突变作为显性负二聚与野生型TRAF 7和破坏其功能，并归因于一个独特的作用，TRAF 7在纤毛发生和鞭毛内运输。虽然TRAF 7（肿瘤坏死因子受体相关因子7）的体细胞变异是前颅底脑膜瘤的基础，但我们在此报告TRAF 7的遗传性突变导致先天性心脏缺陷。我们发现TRAF 7突变体以显性方式运作，通过与野生型蛋白质的异二聚化抑制蛋白质功能。此外，这两种不同病理的共同遗传学可以追溯到来自TRAF 7表达神经嵴的前脑脑膜和心脏流出道的共同起源。体细胞和遗传性突变破坏TRAF 7-IFFT 57相互作用，导致纤毛降解。TRAF 7突变脑膜瘤原代培养缺乏纤毛，TRAF 7敲低导致爪蟾和斑马鱼的心脏，颅面和纤毛缺陷，表明TRAF 7驱动的脑膜瘤和发育性心脏缺陷的机制趋同。
The genetic basis for the increased risk of cancer with congenital heart disease (CHD) is largely unclear. Our study is significant because it identifies TRAF7 (Tumor necrosis factor receptor-associated factor 7) mutations in both, brain tumors (meningiomas) and CHD. While somatic mutations in TRAF7 underlie anterior skull-base meningiomas, here we report the inherited mutations of TRAF7 that cause CHD and show that the shared genetics of the two disparate pathologies can be traced to the common developmental origin of the two tissues from the neural crest. We demonstrate that these mutations act as dominant negative by dimerizing with wild-type TRAF7 and disrupting its function and ascribe a unique role for TRAF7 in ciliogenesis and intraflagellar transport. While somatic variants of TRAF7 (Tumor necrosis factor receptor-associated factor 7) underlie anterior skull-base meningiomas, here we report the inherited mutations of TRAF7 that cause congenital heart defects. We show that TRAF7 mutants operate in a dominant manner, inhibiting protein function via heterodimerization with wild-type protein. Further, the shared genetics of the two disparate pathologies can be traced to the common origin of forebrain meninges and cardiac outflow tract from the TRAF7-expressing neural crest. Somatic and inherited mutations disrupt TRAF7–IFT57 interactions leading to cilia degradation. TRAF7-mutant meningioma primary cultures lack cilia, and TRAF7 knockdown causes cardiac, craniofacial, and ciliary defects in Xenopus and zebrafish, suggesting a mechanistic convergence for TRAF7-driven meningiomas and developmental heart defects.
登录
查看更多内容
影响因子：
2.7
作者：
Grimes, Daniel T.;Patterson, Victoria L.;Burdine, Rebecca D.
通讯作者：
Burdine, Rebecca D.
影响因子：
2.7
作者：
Kawasumi A;Nakamura T;Iwai N;Yashiro K;Saijoh Y;Belo JA;Shiratori H;Hamada H
通讯作者：
Hamada H
DOI：
10.1038/modpathol.2017.153
发表时间：
2018-04
期刊：
Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc
影响因子：
--
作者：
Goode B;Joseph NM;Stevers M;Van Ziffle J;Onodera C;Talevich E;Grenert JP;Yeh I;Bastian BC;Phillips JJ;Garg K;Rabban JT;Zaloudek C;Solomon DA
通讯作者：
Solomon DA
影响因子：
4.6
作者：
Deniz E;Jonas S;Hooper M;N Griffin J;Choma MA;Khokha MK
通讯作者：
Khokha MK
影响因子：
16.6
作者：
Eguether, Thibaut;Ermolaeva, Maria A.;Tassin, Anne-Marie
通讯作者：
Tassin, Anne-Marie