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Proc Natl Acad Sci U S A 2023 Apr 18;12016:e2214997120. doi: 10.1073/pnas.2214997120.
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Pleiotropic role of TRAF7 in skull-base meningiomas and congenital heart disease.

Mishra-Gorur K , Barak T , Kaulen LD , Henegariu O , Jin SC , Aguilera SM , Yalbir E , Goles G , Nishimura S , Miyagishima D , Djenoune L , Altinok S , Rai DK , Viviano S , Prendergast A , Zerillo C , Ozcan K , Baran B , Sencar L , Goc N , Yarman Y , Ercan-Sencicek AG , Bilguvar K , Lifton RP , Moliterno J , Louvi A , Yuan S , Deniz E , Brueckner M , Gunel M .

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.

PubMed ID: 37043537
PMC ID: PMC10120005
Article link: Proc Natl Acad Sci U S A
Grant support: [+]

Species referenced: Xenopus tropicalis
Genes referenced: akt1 arl13b ctrl ift43 ift57 ift80 kdr klf4 nf2 npat pitx2 polr2a smo sox10 traf7 twist1
Morpholinos: traf7 MO1 traf7 MO2 traf7 cMO3
gRNAs referenced: traf7 gRNA1 traf7 gRNA2 traf7 gRNA3

Disease Ontology terms: ciliopathy [+]
Phenotypes: Xtr Wt + traf1 (Fig. 2. R, T') [+]

Article Images: [+] show captions