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

Proc Natl Acad Sci U S A. 2023 Apr 18;120(16):e2214997120. doi: 10.1073/pnas.2214997120. Epub 2023 Apr 12.

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.

Keywords: TRAF7; cilia; congenital heart defect; meningioma.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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

Substances

  • Adaptor Proteins, Signal Transducing
  • IFT57 protein, zebrafish
  • Zebrafish Proteins
  • TRAF7 protein, human
  • Tumor Necrosis Factor Receptor-Associated Peptides and Proteins