Alternative titles; symbols
HGNC Approved Gene Symbol: TRAF7
Cytogenetic location: 16p13.3 Genomic coordinates (GRCh38): 16:2,155,782-2,178,129 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16p13.3 | Cardiac, facial, and digital anomalies with developmental delay | 618164 | Autosomal dominant | 3 |
The TRAF7 gene encodes a member of a family of proteins known as tumor necrosis factor (TNF; see 191160) receptor-associated factors, which are signal transducers for members of the TNF receptor superfamily. TRAF7 is a known mediator of the MAPK (see 601335) and NFKB (see 164011) signaling pathways and is involved in multiple biologic processes, such as ubiquitination (summary by Tokita et al., 2018).
TRAFs are composed of an N-terminal cysteine/histidine-rich region containing zinc RING and/or zinc finger motifs; a coiled-coil (leucine zipper) motif; and a homologous region that defines the TRAF family, the TRAF domain, which is involved in self-association and receptor binding (summary by Bouwmeester et al., 2004).
Using an integrated approach comprising tandem affinity purification, liquid chromatography mass spectrometry, network analysis, and directed functional perturbation studies with RNA interference (RNAi) to map the TNF/NFKB (see 164011) pathway, Bouwmeester et al. (2004) identified RFWD1, which they termed TRAF7, as an interactor with MEKK3 (MAP3K3; 602539). The predicted 670-amino acid protein has an N-terminal RING finger domain, followed by a noncanonical TRAF domain, a coiled-coil (CC) domain, and 7 C-terminal WD40 repeats.
By mutation and coimmunoprecipitation analysis, Bouwmeester et al. (2004) determined that the WD40 repeats of TRAF7 bind MEKK3, whereas homodimerization of TRAF7 occurs through the central TRAF and CC domains. Fluorescence microscopy demonstrated TRAF7 localization in a vesicular pattern in the cytosol in the presence or absence of MEKK3. SDS-PAGE analysis suggested that MEKK3 phosphorylates sites in the N-terminal region of TRAF7 and induces ubiquitination. In the presence of E1 (UBE1; 314370) and E2 (see UBE2E2; 602163) activating and conjugating enzymes, a TRAF7 fragment containing the RING domain was ubiquitinated, indicating that TRAF7 may have E3 ubiquitin ligase (see UBE3A; 601623) activity. Luciferase reporter and RNAi analysis established that coexpression of wildtype TRAF7 and MEKK3 resulted in a synergistic activation of NFKB and AP1 (165160). Bouwmeester et al. (2004) proposed that TRAF7, in conjunction with MEKK3, might act like TAK1 (MAP3K7; 602614) and TRAF6 (602355) in relaying signals, impinging on the activation of JNK (601158) and p38 MAP kinases (see MAPK14; 600289), most likely by means of intermediate effectors.
Tokita et al. (2018) stated that the TRAF7 gene contains 21 exons.
Tokita et al. (2018) stated that the TRAF7 gene resides on chromosome 16p13.3.
In 7 unrelated patients with cardiac, facial, and digital anomalies with developmental delay (CAFDADD; 618164), Tokita et al. (2018) identified de novo heterozygous missense mutations in the TRAF7 gene (606692.0001-606692.0004). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, were not found in the ExAC or gnomAD databases. Four patients carried the same mutation (R655Q; 606692.0001). Two of the mutations occurred in WD40 domains and 2 in coiled-coil regions, both of which are functionally important. In vitro functional expression assays in HEK293 cells showed that the mutations resulted in variably decreased ERK1/ERK2 (MAPK3; 601795/MAPK1; 176948) phosphorylation after TNF-alpha (191160) stimulation compared to controls.
In 4 unrelated patients (subjects 1 through 4) with cardiac, facial, and digital anomalies with developmental delay (CAFDADD; 618164), Tokita et al. (2018) identified a de novo heterozygous c.1964G-A transition (c.1964G-A, NM_032271.2) in exon 20 of the TRAF7 gene, resulting in an arg655-to-gln (R655Q) substitution at a conserved reside in the seventh WD40 domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC or gnomAD databases. Tokita et al. (2018) noted that Krumm et al. (2015) had identified a de novo heterozygous R655Q mutation in the TRAF7 gene in a patient with autism who was part of a cohort of 2,377 families with autism.
In a 1-week-old boy (subject 5) with cardiac, facial, and digital anomalies with developmental delay (CAFDADD; 618164), Tokita et al. (2018) identified a de novo heterozygous c.1801A-G transition (c.1801A-G, NM_032271.2) in exon 19 of the TRAF7 gene, resulting in a thr601-to-ala (T601A) substitution at a highly conserved residue in the sixth WD40 domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC or gnomAD databases.
In a 20-month-old girl (subject 6) with cardiac, facial, and digital anomalies with developmental delay (CAFDADD; 618164), Tokita et al. (2018) identified a de novo heterozygous c.1036A-G transition (c.1036A-G, NM_032271.2) in exon 11 of the TRAF7 gene, resulting in a lys346-to-glu (K346E) substitution at a highly conserved residue in the coiled-coil domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC or gnomAD databases.
In an 8-year-old boy (subject 7) with cardiac, facial, and digital anomalies with developmental delay (CAFDADD; 618164), Tokita et al. (2018) identified a de novo heterozygous c.1111C-G transversion (c.1111C-G, NM_032271.2) in exon 12 of the TRAF7 gene, resulting in an arg371-to-gly (R371G) substitution at a highly conserved residue in the coiled-coil domain. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in the ExAC or gnomAD databases. The patient was found to be mosaic for the mutation, with the mutation having an allele frequency of about 15% in peripheral blood cells. Tokita et al. (2018) stated that the phenotype of this patient was not milder compared to others with TRAF7 mutations; however, he did not have cardiac abnormalities.
Bouwmeester, T., Bauch, A., Ruffner, H., Angrand, P.-O., Bergamini, G., Croughton, K., Cruciat, C., Eberhard, D., Gagneur, J., Ghidelli, S., Hopf, C., Huhse, B., and 16 others. A physical and functional map of the human TNF-alpha/NF-kappa-B signal transduction pathway. Nature Cell Biol. 6: 97-105, 2004. Note: Erratum: Nature Cell Biol. 6: 465 only, 2004. [PubMed: 14743216] [Full Text: https://doi.org/10.1038/ncb1086]
Krumm, N., Turner, T. N., Baker, C., Vives, L., Mohajeri, K., Witherspoon, K., Raja, A., Coe, B. P., Stessman, H. A., He, Z.-X., Leal, S. M., Bernier, R., Eichler, E. E. Excess of rare, inherited truncating mutations in autism. Nature Genet. 47: 582-588, 2015. [PubMed: 25961944] [Full Text: https://doi.org/10.1038/ng.3303]
Tokita, M. J., Chen, C.-A., Chitayat, D., Macnamara, E., Rosenfeld, J. A., Hanchard, N., Lewis, A. M., Brown, C. W., Marom, R., Shao, Y., Novacic, D., Wolfe, L., and 25 others. De novo missense variants in TRAF7 cause developmental delay, congenital anomalies, and dysmorphic features. Am. J. Hum. Genet. 103: 154-162, 2018. [PubMed: 29961569] [Full Text: https://doi.org/10.1016/j.ajhg.2018.06.005]