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

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.

Automated summary

In this study, somatic variants of the TRAF7 gene were found to be responsible for anterior skull-base meningiomas, while inherited mutations of TRAF7 were identified to cause congenital heart defects. The dominant effect of TRAF7 mutants was demonstrated, as they inhibited protein function by heterodimerizing with wild-type protein. The common genetic origin of the two different pathologies was traced back to the TRAF7-expressing neural crest, which gives rise to forebrain meninges and the cardiac outflow tract. Somatic and inherited mutations disrupted TRAF7-IFT57 interactions, leading to cilia degradation. The lack of cilia in TRAF7-mutant meningioma primary cultures and the development of cardiac, craniofacial, and ciliary defects in Xenopus and zebrafish upon TRAF7 knockdown suggest a mechanistic convergence between TRAF7-driven meningiomas and developmental heart defects.