Department of Neurosurgery, Yale School of Medicine, New Haven, CT 06510.
Department of Genetics, Yale School of Medicine, New Haven, CT 06510.
Proc Natl Acad Sci U S A. 2023 Apr 18;120(16):e2214997120. doi: 10.1073/pnas.2214997120. Epub 2023 Apr 12.
While somatic variants of (Tumor necrosis factor receptor-associated factor 7) underlie anterior skull-base meningiomas, here we report the inherited mutations of 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 expressing neural crest. Somatic and inherited mutations disrupt TRAF7-IFT57 interactions leading to cilia degradation. -mutant meningioma primary cultures lack cilia, and TRAF7 knockdown causes cardiac, craniofacial, and ciliary defects in and zebrafish, suggesting a mechanistic convergence for -driven meningiomas and developmental heart defects.
尽管（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，但在这里我们报告了导致先天性心脏缺陷的 遗传突变。我们表明，TRAF7 突变体以显性方式起作用，通过与野生型蛋白形成异二聚体来抑制蛋白功能。此外，两种截然不同的病理的共同遗传可以追溯到头脑前部脑膜和心脏流出道从表达神经嵴的共同起源。体细胞和遗传突变破坏了 TRAF7-IFT57 相互作用，导致纤毛降解。 -突变脑膜瘤原代培养物缺乏纤毛，而 TRAF7 敲低会导致 和斑马鱼的心脏、颅面和纤毛缺陷，这表明 驱动的脑膜瘤和发育性心脏缺陷存在机制趋同。
