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

Abstract

While somatic variants ofTRAF7 (Tumor necrosis factorreceptor-associatedfactor7) underlie anterior skull-base meningiomas, here we report the inherited mutations ofTRAF7that 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 inXenopus and zebrafish, suggesting a mechanistic convergence forTRAF7-driven meningiomas and developmental heart defects.