RESUMO
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.
Assuntos
Cardiopatias Congênitas , Neoplasias Meníngeas , Meningioma , Animais , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Cardiopatias Congênitas/genética , Neoplasias Meníngeas/genética , Meningioma/genética , Meningioma/patologia , Mutação , Crânio/metabolismo , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genética , Humanos , Peptídeos e Proteínas Associados a Receptores de Fatores de Necrose TumoralRESUMO
Programs to increase emerging and established HIV and tuberculosis (TB) researchers' capacity to be more effective leaders and mentors are urgently needed in low- and middle-income countries (LMICs). Although conceptual frameworks of mentoring and mentoring toolkits have been developed by and for researchers in LMIC settings, few mentor training programs have been implemented and evaluated in these settings. We created, implemented, and evaluated a 9-month, certificate-level mentorship training program to strengthen the pipeline of HIV and TB researchers in South Africa. Differentiating features of the program included careful contextualization of mentorship tools and approaches, inclusion of a leadership curriculum to improve participant ability to work effectively in teams and organizations, and attention to processes that promote interinstitutional collaboration in mentorship. Twelve mid-career researchers graduated from the first cohort of the program. Among participants, we observed significant longitudinal improvement in mentorship competencies, increased numbers of network connections in multiple domains of collaboration, and high levels of satisfaction. We anticipate that the program description and results will be useful to researchers, research institutions, and funders seeking to build research mentorship and leadership capacity in LMIC settings.