TRAF7 is a protein that consists of several functional domains. It possesses an N-terminal RING finger domain, a TRAF-type zinc finger adjacent to it, a coiled-coil domain, and seven C-terminal WD40 repeats. Like other TRAF members, TRAF7 exhibits E3 ubiquitin ligase activity, which can initiate downstream signalling events. These signalling pathways play roles in diverse cellular processes such as cell survival, proliferation, migration, differentiation, cytokine production, and autophagy. Activation of TRAF7 occurs through homodimerization mediated by its zinc fingers and coiled-coil domains, while the WD40 repeats domain is essential for its interaction with MEKK3 and subsequent self-ubiquitination.
To date, all reported pathogenic variants associated with TRAF7 syndrome are heterozygous missense mutations, primarily occurring de novo. There have been a few exceptional cases, including a family in which dizygotic twins inherited the TRAF7 variant from their mildly affected mother, who acquired the variant de novo, as well as another family with a mildly affected mosaic mother and her son. The majority of these variants are located within the C-terminal region of the protein, specifically within the WD40 domains, while a few have been reported in the coiled-coil domain. The exact physiological mechanism of action remains unclear.
TRAF7