TRAF7 contains an N-terminal RING finger domain, an adjacent TRAF-type zinc finger, a coiled-coil domain, and seven C-terminal WD40 repeats in spite of the typical C-terminal TRAF domain characteristic of the TRAF protein family. TRAF proteins act as signaling adaptors directly binding to the cytoplasmatic domain of receptors of several families. TRAF7, as other TRAF members, have E3 ubiquitin ligase activity that can activate downstream signaling events. The signaling pathways in which these proteins participate are involved in a wide range of cellular processes, such as cell survival, proliferation, migration, differentiation, cytokine production and autophagy. Tumour necrosis factor (TNF) family ligands lead to the transduction of these cellular signals through activation of different effectors, such as nuclear factor-κBs (NF-κBs), mitogen-activated protein kinases (MAPKs), or interferon-regulatory factors (IRFs). TRAF7 activation involves homodimerization through its Zn fingers and coiled-coil domains while the WD40 repeats domain is crucial for the interaction of TRAF7 with MEKK3, and subsequent selfubiquitination.
So far, all reported TRAF7 syndrome pathogenic variants are germline heterozygous missense mutations, mostly de novo . One family has been reported in which affected dizygotic twins inherited a TRAF7 variant from their mildly affected mother, in whom the variant arose de novo as well as a second family with a mildly affected mosaic mother and her son. Most of the variants lay within the C-terminal portion of the protein, at the WD40 domains, and a few have been reported at the coiled-coil domain. The physiological mechanism of action is still unclear but the kind of variant and the lack of Loss of Function (LoF) mutations linked to TRAF7 syndrome so far suggest a complex molecular mechanism further than a simple loss of function mechanism.
TRAF7