TY - JOUR
T1 - Pleiotropic role of TRAF7 in skull-base meningiomas and congenital heart disease
AU - Mishra-Gorur, Ketu
AU - Barak, Tanyeri
AU - Kaulen, Leon D.
AU - Henegariu, Octavian
AU - Jin, Sheng Chih
AU - Aguilera, Stephanie Marie
AU - Yalbir, Ezgi
AU - Goles, Gizem
AU - Nishimura, Sayoko
AU - Miyagishima, Danielle
AU - Djenoune, Lydia
AU - Altinok, Selin
AU - Rai, Devendra K.
AU - Viviano, Stephen
AU - Prendergast, Andrew
AU - Zerillo, Cynthia
AU - Ozcan, Kent
AU - Baran, Burcin
AU - Sencar, Leman
AU - Goc, Nukte
AU - Yarman, Yanki
AU - Ercan-Sencicek, A. Gulhan
AU - Bilguvar, Kaya
AU - Lifton, Richard P.
AU - Moliterno, Jennifer
AU - Louvi, Angeliki
AU - Yuan, Shiaulou
AU - Deniz, Engin
AU - Brueckner, Martina
AU - Gunel, Murat
N1 - Funding Information:
We would like to acknowledge the efforts and invaluable support of the operating room team at Yale New Haven Hospital in helping procure tumor samples for this study. We thank the Center for Cellular and Molecular Imaging, Electron Microscopy Facility at Yale Medical School, for assistance with the work presented here. This work was supported by the James Hudson Brown-Alexander Brown Coxe Postdoctoral Fellowship, an American Heart Association Postdoctoral Fellowship, and the National Heart, Lung, and Blood Institute of the NIH Award Number K99HL143036 (to S.C.J); NIH grant 1R01HL165241-01, Charles Hood Foundation and American Heart Association (to S.Y.); American Heart Association Postdoctoral Fellowship (to L.D.); NIH grant R21NS116484-02 and R01NS127879-01 (to E.D); Yale University funds, Gregory M. Kiez and Mehmet Kutman Foundation, and NIH grant 1R01NS110824-01A1 (for elucidating the molecular mechanism of TRAF7 in meningiomas only) (to M.G.)
Funding Information:
ACKNOWLEDGMENTS. We would like to acknowledge the efforts and invaluable support of the operating room team at Yale New Haven Hospital in helping procure tumor samples for this study.We thank the Center for Cellular and Molecular Imaging, Electron Microscopy Facility at Yale Medical School, for assistance with the work presented here.This work was supported by the James Hudson Brown– Alexander Brown Coxe Postdoctoral Fellowship, an American Heart Association Postdoctoral Fellowship, and the National Heart, Lung, and Blood Institute of the NIH Award Number K99HL143036 (to S.C.J); NIH grant 1R01HL165241-01, Charles Hood Foundation and American Heart Association (to S.Y.); American Heart Association Postdoctoral Fellowship (to L.D.); NIH grant R21NS116484-02 and R01NS127879-01 (to E.D); Yale University funds, Gregory M. Kiez and Mehmet Kutman Foundation, and NIH grant 1R01NS110824-01A1 (for elucidating the molecular mechanism of TRAF7 in meningiomas only) (to M.G.)
Publisher Copyright:
Copyright © 2023 the Author(s). Published by PNAS. This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
PY - 2023/4/18
Y1 - 2023/4/18
N2 - 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.
AB - 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.
KW - TRAF7
KW - cilia
KW - congenital heart defect
KW - meningioma
UR - http://www.scopus.com/inward/record.url?scp=85152482360&partnerID=8YFLogxK
U2 - 10.1073/pnas.2214997120
DO - 10.1073/pnas.2214997120
M3 - Article
C2 - 37043537
AN - SCOPUS:85152482360
SN - 0027-8424
VL - 120
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 16
M1 - e2214997120
ER -