Alternative titles; symbols
HGNC Approved Gene Symbol: TRAF3IP1
Cytogenetic location: 2q37.3 Genomic coordinates (GRCh38): 2:238,320,518-238,400,900 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q37.3 | Senior-Loken syndrome 9 | 616629 | Autosomal recessive | 3 |
The TRAF3IP1 gene encodes the homolog of intraflagellar transport protein IFT54, a subunit of the IFT-B complex that mediates anterograde transport in cilia (summary by Bizet et al., 2015).
Using TRAF3 (601896) as bait in a yeast 2-hybrid screen, Ling and Goeddel (2000) obtained a partial MIPT3 sequence, which they used as probe to obtain the full-length cDNA from a HeLa cell cDNA library. The deduced 625-amino acid protein contains a KKE motif and a C-terminal coiled-coil domain. Northern blot analysis revealed expression of 4.4- and 2.4-kb transcripts in all tissues examined. Testis also expressed a 2.7-kb transcript. Ling and Goeddel (2000) determined that the 4.4- and 2.4-kb transcripts encode the same open reading frame, with the longer transcript containing an extra 2 kb of 3-prime untranslated region. Western blot analysis revealed that endogenous MIPT3 has an apparent molecular mass of 83 kD.
Berbari et al. (2011) found that Traf3ip1 localized to the ciliary axoneme and basal body in mouse renal collecting duct cells.
Bizet et al. (2015) found that the IFT54 protein localized to the base and tip of cilia in mouse inner medullary collecting duct cells. It was present at the ciliary transition fibers/transition zone at the base of cilia, where it colocalized with the distal appendage protein CEP164 (614848), as well as at the proximal part of the centrioles.
Scott (2002) mapped the MIPT3 gene to chromosome 2q37.3 based on sequence similarity between the MIPT3 sequence (GenBank AF230877) and the chromosome 2 clones RP11-7908 (GenBank AC013400) and RP11-40B20 (GenBank AC016999).
Using in vitro pull-down assays and coimmunoprecipitation studies, Ling and Goeddel (2000) determined that the interaction between MIPT3 and TRAF3 is specific. MIPT3 did not significantly interact with any other TRAF family members tested. By in vitro binding studies of truncated proteins, Ling and Goeddel (2000) found that the interaction required the coiled-coil TRAF-N domain of TRAF3 and the C-terminal coiled-coil domain of MIPT3. When expressed separately, both MIPT3 and TRAF3 showed a cytosolic localization, but when coexpressed, both proteins colocalized with tubulin (see 191130) in cytoskeletal structures. MIPT3 bound to Taxol-stabilized microtubules and to tubulin in vitro, and MIPT3 recruited TRAF3 to microtubules when both proteins were overexpressed in HeLa cells. Mutation analysis of in vitro translated MIPT3 revealed that the tubulin-binding domain of MIPT3 resides within the N-terminal region.
Omori et al. (2008) identified elipsa, the zebrafish ortholog of TRAF3IP1, as a component of intraflagellar transport particles, which are involved in the formation and function of cilia. Elipsa interacted with rabaptin-5 (RABEP1; 603616), a regulator of endocytosis, and rabaptin-5 in turn interacted with Rab8 (RAB8A; 165040), a small GTPase localized to cilia. Omori et al. (2008) concluded that elipsa, rabaptin-5, and Rab8 provide a bridge between the intraflagellar transport particle and protein complexes that assemble at the ciliary membrane.
Senior-Loken Syndrome 9
In 8 patients from 5 unrelated families with Senior-Loken syndrome-9 (SLNS9; 616629), Bizet et al. (2015) identified homozygous or compound heterozygous mutations in the TRAF3IP1 gene (607380.0001-607380.0006). The mutations were found by a combination of linkage analysis and whole-exome sequencing. Expression of the mutations in traf3ip1 morphant zebrafish embryos failed to rescue the ciliopathy phenotype, consistent with the mutations resulting in decreased protein function. Immunohistochemical studies of patient fibroblasts showed absence of IFT54 staining at the transition zone and tip of cilia. Patient cilia were longer than those of controls, but there was no difference in the percentage of ciliated cells, in the localization of key ciliary proteins, or in general ciliary composition. However, patient cilia showed a decrease of adenylyl cyclase III (ADCY3; 600291) and impaired translocation of protein kinase A catalytic subunits (e.g., PRKACA, 601639) from the cilium base to the cytoplasm. Missense mutations were associated with impaired IFT54 localization along cytoplasmic microtubules and with a loss of interaction between IFT54 and MAP4 (157132). Patient kidney tubules and fibroblasts showed increased acetylation of alpha-tubulin that correlated with enhanced MAP4 and increased microtubule stabilization. These defects in microtubule dynamics were associated with loss of apicobasal polarity in epithelialized kidney cells. The findings suggested a role for TRAF3IP1 as a negative regulator of microtubule stability via regulation of MAP4.
Associations Pending Confirmation
For discussion of a possible association between variation in the TRAF3IP1 gene and furrow contractions in the iris, see 610744.
Knockdown of the traf3ip1 homolog 'elipsa' in zebrafish is embryonic lethal and is associated with curved body axis, pronephric cysts, and loss of photoreceptor cells in the retina (Omori et al., 2008; Bizet et al., 2015).
Berbari et al. (2011) found that homozygous loss of the Traf3ip1 gene in mice was embryonic lethal. Mutant mice showed neural developmental defects, cardiac edema, polydactyly, and variable microphthalmia, consistent with ciliary assembly defects. Mutant mice also showed abnormal dorsal-ventral neural tube patterning and diminished expression of a Shh (600725) reporter. Cells derived from mutant mice were unable to form cilia and showed increased cytosolic levels of acetylated microtubules. There was also a marked increase in cell size in culture associated with increased activation of the Mtor (601231) pathway. The findings indicated that Traf3ip1 function is highly conserved in ciliogenesis and is important for proper regulation of a number of essential developmental and cellular pathways.
In a girl from Mali (family NPH638) with Senior-Loken syndrome-9 (SLSN9; 616629), Bizet et al. (2015) identified compound heterozygous mutations in the TRAF3IP1 gene: a c.374T-C transition (c.374T-C, NM_015650.3) in exon 4 of the TRAF3IP1 gene, resulting in a val125-to-ala (V125A) substitution at a highly conserved residue, and a c.463C-T transition in exon 4, resulting in an arg155-to-ter (R155X; 607380.0002) substitution. The mutations, which were found by a combination of linkage analysis and whole-exome sequencing, were confirmed by Sanger sequencing and segregated with the disorder in the family. Neither mutation was found in the ExAC database.
For discussion of the c.463C-T transition (c.463C-T, NM_015650.3) in the TRAF3IP1 gene, resulting in an arg155-to-ter (R155X; 607380.0002) substitution, that was found in compound heterozygous state in a patient with Senior-Loken syndrome-9 (SLSN9; 616629) by Bizet et al. (2015), see 607380.0001.
In 2 Portuguese brothers, born of probably consanguineous parents (family NPH579), with Senior-Loken syndrome-9 (SLSN9; 616629), Bizet et al. (2015) identified a homozygous c.1559T-G transversion (c.1559T-G, NM_015650.3) in exon 13 of the TRAF3IP1 gene, resulting in a met520-to-arg (M520R) substitution at a conserved residue. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, was confirmed by Sanger sequencing and segregated with the disorder in the family. It was found once in the ExAC database (1 of 119,598 alleles). The patients had additional clinical features, including developmental delay, obesity, and polydactyly, reminiscent of Bardet-Biedl syndrome (see, e.g., BBS1, 209900).
In an Italian patient, born of consanguineous parents (family NPH1110), with Senior-Loken syndrome-9 (SLSN9; 616629), Bizet et al. (2015) identified a homozygous T-to-G transversion (c.1575+6T-G, NM_015650.3) in intron 13 of the TRAF3IP1 gene, resulting in creation of a new donor splice site, premature termination (Met525MetfsTer3), and nonsense-mediated mRNA decay. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, was confirmed by Sanger sequencing and segregated with the disorder in the family. It was not found in the ExAC database.
In 3 brothers, born of consanguineous Moroccan parents (family NPH302), with Senior-Loken syndrome-9 (SLSN9; 616629), Bizet et al. (2015) identified a homozygous c.373G-A transition (c.373G-A, NM_015650.3) in exon 4 of the TRAF3IP1 gene, resulting in a val125-to-met (V125M) substitution at a highly conserved residue. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, was confirmed by Sanger sequencing and segregated with the disorder in the family. It was not found in the ExAC database.
In a girl, born of consanguineous Egyptian parents (family A4336), with Senior-Loken syndrome-9 (SLSN9; 616629), Bizet et al. (2015) identified a homozygous c.51T-G transversion (c.51T-G, NM_015650.3) in exon 1 of the TRAF3IP1 gene, resulting in an ile17-to-ser (I17S) substitution at a highly conserved residue. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing, was confirmed by Sanger sequencing and segregated with the disorder in the family. It was not found in the ExAC database.
Berbari, N. F., Kin, N. W., Sharma, N., Michaud, E. J., Kesterson, R. A., Yoder, B. K. Mutations in Traf3ip1 reveal defects in ciliogenesis, embryonic development, and altered cell size regulation. Dev. Biol. 360: 66-76, 2011. [PubMed: 21945076] [Full Text: https://doi.org/10.1016/j.ydbio.2011.09.001]
Bizet, A. A., Becker-Heck, A., Ryan, R., Weber, K., Filhol, E., Krug, P., Halbritter, J., Delous, M., Lasbennes, M.-C., Linghu, B., Oakeley, E. J., Zarhrate, M., and 22 others. Mutations in TRAF3IP1/IFT54 reveal a new role for IFT proteins in microtubule stabilization. Nature Commun. 6: 8666, 2015. Note: Electronic Article. [PubMed: 26487268] [Full Text: https://doi.org/10.1038/ncomms9666]
Ling, L., Goeddel, D. V. MIP-T3, a novel protein linking tumor necrosis factor receptor-associated factor 3 to the microtubule network. J. Biol. Chem. 275: 23852-23860, 2000. [PubMed: 10791955] [Full Text: https://doi.org/10.1074/jbc.M001095200]
Omori, Y., Zhao, C., Saras, A., Mukhopadhyay, S., Kim, W., Furukawa, T., Sengupta, P., Veraksa, A., Malicki, J. elipsa is an early determinant of ciliogenesis that links the IFT particle to membrane-associated small GTPase Rab8. Nature Cell Biol. 10: 437-444, 2008. [PubMed: 18364699] [Full Text: https://doi.org/10.1038/ncb1706]
Scott, A. F. Personal Communication. Baltimore, Md. 11/25/2002.