Pleiotropic role of TRAF7 in skull-base meningiomas and congenital heart disease.

Abstract

While somatic variants of <i>TRAF7</i> (Tumor necrosis factor receptor-associated factor 7) underlie anterior skull-base meningiomas, here we report the inherited mutations of <i>TRAF7</i> 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 <i>TRAF7-</i>expressing neural crest. Somatic and inherited mutations disrupt TRAF7-IFT57 interactions leading to cilia degradation. <i>TRAF7</i>-mutant meningioma primary cultures lack cilia, and TRAF7 knockdown causes cardiac, craniofacial, and ciliary defects in <i>Xenopus</i> and zebrafish, suggesting a mechanistic convergence for <i>TRAF7</i>-driven meningiomas and developmental heart defects.