PUBLICATION

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

Authors
Mishra-Gorur, K., Barak, T., Kaulen, L.D., Henegariu, O., Jin, S.C., Aguilera, S.M., Yalbir, E., Goles, G., Nishimura, S., Miyagishima, D., Djenoune, L., Altinok, S., Rai, D.K., Viviano, S., Prendergast, A., Zerillo, C., Ozcan, K., Baran, B., Sencar, L., Goc, N., Yarman, Y., Ercan-Sencicek, A.G., Bilguvar, K., Lifton, R.P., Moliterno, J., Louvi, A., Yuan, S., Deniz, E., Brueckner, M., Gunel, M.
ID
ZDB-PUB-230413-50
Date
2023
Source
Proceedings of the National Academy of Sciences of the United States of America   120: e2214997120e2214997120 (Journal)
Registered Authors
Keywords
TRAF7, cilia, congenital heart defect, meningioma
MeSH Terms
  • Adaptor Proteins, Signal Transducing/metabolism
  • Animals
  • Heart Defects, Congenital*/genetics
  • Humans
  • Meningeal Neoplasms*/genetics
  • Meningioma*/genetics
  • Meningioma*/pathology
  • Mutation
  • Skull/metabolism
  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins
  • Zebrafish/genetics
  • Zebrafish/metabolism
  • Zebrafish Proteins/genetics
PubMed
37043537 Full text @ Proc. Natl. Acad. Sci. USA
Abstract
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.
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