Alternative titles; symbols
HGNC Approved Gene Symbol: TRIOBP
Cytogenetic location: 22q13.1 Genomic coordinates (GRCh38) : 22:37,697,048-37,776,556 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 22q13.1 | Deafness, autosomal recessive 28 | 609823 | Autosomal recessive | 3 |
Using a portion of TRIO (601893) as bait in a yeast interaction trap assay of a human fibroblast cDNA library, followed by screening a skeletal muscle cDNA library, Seipel et al. (2001) cloned TRIOBP, which they called TARA. TARA contains an N-terminal pleckstrin homology (PH) domain and a C-terminal coiled-coil region. Northern blot analysis detected broad expression of TARA, with highest levels in heart and placenta. The major transcript was 2.8 kb, and minor transcripts of 2.0 to 4.4 kb were present in several tissues. Western blot analysis of HeLa cell lysates detected endogenous TARA at an apparent molecular mass of 80 kD.
Both Shahin et al. (2006) and Riazuddin et al. (2006) described complex alternative splicing of the TRIOBP gene. Shahin et al. (2006) described a long isoform of 2,267 amino acids; the longest isoform found by Riazuddin et al. (2006) consisted of 2,365 amino acids. Depending on the isoform, TRIOBP has 5 copies each of 2 repeated motifs encoded by exon 6, a predicted PH domain, and 4 coiled-coil regions (Riazuddin et al., 2006). Shahin et al. (2006) observed expression of the TRIOBP long isoform in fetal brain, retina, and cochlea.
Kitajiri et al. (2010) stated that TRIOBP isoforms are produced through the use of 2 alternate promoters and can be grouped into 3 classes. The first TRIOBP5 is the longest transcript that utilize a distal promoter upstream of exon 1, terminate in exon 24, and has a molecular mass of 218-kD in humans. The second TRIOBP4 terminates after exon 6 and encodes a shorter protein product that contains the repeat motifs of exon 6 but none of the C domains of TRIOBP-5, and has a molecular mass of 107-kD. The third TRIOBP1 has a molecular mass of 72-kD, is initiated from a promoter downstream of exon 6, and encodes a protein that does not contain the N-terminal internal repeat motifs, but does include the C domains of TRIOBP5 encoded by exons 11 to 24. TRIOBP1 was the transcript identified by Seipel et al. (2001). Thus, TRIOBP1 and TRIOBP4 share no exons or amino acid-coding sequence. TRIOBP1 shows ubiquitous expression, whereas TRIOBP4 and TRIOBP5 are expressed predominantly in the eye and inner ear. Kitajiri et al. (2010) noted that, to date, all of the mutations of TRIOBP causing human deafness DFNB28 (609823) are located in exon 6 and only affect the TRIOBP4 and TRIOBP5 isoforms.
Kitajiri et al. (2010) noted that the TRIOBP gene contains 24 exons.
By genomic sequence analysis, Hirosawa et al. (2001) mapped the TRIOBP gene to chromosome 22q.
Both Riazuddin et al. (2006) and Shahin et al. (2006) mapped a form of recessive nonsyndromic hearing loss, DFNB28 (609823), to 22q13.1 and demonstrated mutations in the TRIOBP gene, which resides in that region. Thus, they established the mapping of the TRIOBP gene to chromosome 22q13.1.
Using several truncation mutants in protein interaction assays, Seipel et al. (2001) demonstrated that the N-terminal half of TARA interacted with the TRIO TGD1 domain, which regulates actin cytoskeletal organization, cell growth, and cell migration. The coiled-coil region of TARA was required for dimerization. TARA also associated with F-actin (see 102610) through an N-terminal sequence, but it did not associate with intermediate filaments or microtubules. TARA localization along actin fibers showed periodicity, and TARA alternated with alpha-actinin (see ACTN1; 102575) along actin fibers, particularly at the leading edge of the cell. Cells transiently or stably overexpressing TARA displayed an extensively flattened morphology with enhanced stress fibers and cortical F-actin. TARA expression did not directly alter cell attachment or initial cell spreading, but it altered the actin cytoskeleton to promote enhanced cell spreading. TARA also stabilized F-actin structures, as indicated by the relative resistance of TARA-expressing cells to an F-actin destabilizer.
In mice, Kitajiri et al. (2010) found Triobp5 staining at the base of stereocilia rootlets of cochlear hair cells beginning at postnatal days 1 to 2. Staining later extended along the mature rootlet in the cuticular plate, but not along the length of the stereocilia. Cosedimentation studies showed that Triobp4 bound to F-actin filaments in dense bundles.
Riazuddin et al. (2006) and Shahin et al. (2006) described mutations of the TRIOBP gene causing recessive nonsyndromic hearing loss designated DFNB28 (609823). Riazuddin et al. (2006) found 4 nonsense mutations and 2 frameshift mutations, all located in exon 6 of TRIOBP. Genetic heterogeneity at this locus was suggested by 5 additional families that showed significant evidence of linkage of deafness to markers on 22q13 but in whom no mutations in the TRIOBP gene were found.
The mutations identified by Shahin et al. (2006) in 9 Palestinian families were located in a novel 218-kD isoform of TRIOBP. Shahin et al. (2006) demonstrated that this long isoform has a restricted expression profile, including cochlea, retina, and fetal brain, whereas the originally described short isoform is widely expressed. Antibodies to TRIOBP revealed expression in sensory cells of the inner ear and colocalization with F-actin along the length of the stereocilia.
Kitajiri et al. (2010) generated a Triobp4/5-deficient mouse recapitulating human DFNB28 deafness. Triobp1-null mice were embryonic lethal, suggesting an essential role in development for this isoform. In Triobp4/5-null mice, rootlets in inner ear hair cells failed to develop, resulting in normal-length stereocilia that were abnormally flexible at the pivot points and were easily damaged by overstimulation. Although mutant hair cells were still able to function in mechanoelectrical transduction prior to the onset of hearing, they were unlikely to have normal mechanosensitivity in vivo due to both decreased pivotal stiffness and increased fragility. The findings indicated that dense bundling of actin filaments by TRIOBP is essential for the biogenesis of rootlets that provide durable flexibility at the taper, and mechanical rigidity to the stereocilia bundle.
In members of a Palestinian Orthodox Christian family with autosomal recessive deafness (DFNB28; 609823), Shahin et al. (2006) found homozygosity for a 1039C-T transition in coding exon 5 of the long TRIOBP isoform. The mutation was predicted to cause an arg347-to-stop (R347X) nonsense mutation. The hearing loss was sensorineural, bilateral, symmetric, and profound. The family traced its ancestry since the mid-18th century to the area of Bethlehem and Beit Sahour in Israel. The R347X mutations was also found in 3 other families from the same Orthodox Christian community.
In 3 Palestinian Muslim families with autosomal recessive deafness (DFNB28; 609823), Shahin et al. (2006) found homozygosity for a 1741C-T transition in exon 5 of the TRIOBP gene that was predicted to result in a gln581-to-ter mutation (Q581X). Both R347X and Q581X led to truncation of the long TRIOBP isoform but were predicted to have no effect on the short TRIOBP isoform, since the latter is transcribed from an alternate first exon.
In an Indian family with autosomal recessive deafness (DFNB28; 609823), Riazuddin et al. (2006) found a nonsense mutation, gln297 to stop (Q297X), in exon 6 of the long isoform of TRIOBP. The mutation arose from a C-to-T transition at nucleotide 889.
In a Pakistani family, Riazuddin et al. (2006) found a nonsense mutation, arg788 to stop (R788X), in exon 6 of the long isoform of TRIOBP as the cause of nonsyndromic recessive deafness (DFNB28; 609823). The mutation arose from a C-to-T transition at nucleotide 2362.
In a Pakistani family, Riazuddin et al. (2006) found a nonsense mutation, arg1068 to stop (R1068X), in exon 6 of the long isoform of TRIOBP as the cause of nonsyndromic recessive deafness (DFNB28; 609823). The mutation arose from a C-to-T transition at nucleotide 3202.
In an Indian family, Riazuddin et al. (2006) found a nonsense mutation, arg1117 to stop (R1117X), in exon 6 of the long isoform of TRIOBP as the cause of nonsyndromic recessive deafness (DFNB28; 609823). The mutation arose from a C-to-T transition at nucleotide 3349.
In an Indian family, Riazuddin et al. (2006) found that nonsyndromic recessive deafness (DFNB28; 609823) was caused by a 2-bp deletion, 3202_3203delCG (Asp1069fsTer1082), in the TRIOBP gene.
In 2 Indian families, Riazuddin et al. (2006) found that individuals with nonsyndromic recessive deafness (DFNB28; 609823) had a frameshift mutation of the TRIOBP gene: 3225_3226insC. The mutation caused a frameshift at arg1078 with a premature termination at residue 1083 (Arg1078fsTer1083).
Hirosawa, M., Nagase, T., Murahashi, Y., Kikuno, R., Ohara, O. Identification of novel transcribed sequences on human chromosome 22 by expressed sequence tag mapping. DNA Res. 8: 1-9, 2001. [PubMed: 11258795] [Full Text: https://doi.org/10.1093/dnares/8.1.1]
Kitajiri, S., Sakamoto, T., Belyantseva, I. A., Goodyear, R. J., Stepanyan, R., Fujiwara, I., Bird, J. E., Riazuddin, S., Riazuddin, S., Ahmed, Z. M., Hinshaw, J. E., Sellers, J., Bartles, J. R., Hammer, J. A., III, Richardson, G. P., Griffith, A. J., Frolenkov, G. I., Friedman, T. B. Actin-bundling protein TRIOBP forms resilient rootlets of hair cell stereocilia essential for hearing. Cell 141: 786-798, 2010. [PubMed: 20510926] [Full Text: https://doi.org/10.1016/j.cell.2010.03.049]
Riazuddin, S., Khan, S. N., Ahmed, Z. M., Ghosh, M., Caution, K., Nazli, S., Kabra, M., Zafar, A. U., Chen, K., Naz, S., Antonellis, A., Pavan, W. J., Green, E. D., Wilcox, E. R., Friedman, P. L., Morell, R. J., Riazuddin, S., Friedman, T. B. Mutations in TRIOBP, which encodes a putative cytoskeletal-organizing protein, are associated with nonsyndromic recessive deafness. Am. J. Hum. Genet. 78: 137-142, 2006. [PubMed: 16385457] [Full Text: https://doi.org/10.1086/499164]
Seipel, K., O'Brien, S. P., Iannotti, E., Medley, Q. G., Streuli, M. Tara, a novel F-actin binding protein, associates with the Trio guanine nucleotide exchange factor and regulates actin cytoskeletal organization. J. Cell Sci. 114: 389-399, 2001. [PubMed: 11148140] [Full Text: https://doi.org/10.1242/jcs.114.2.389]
Shahin, H., Walsh, T., Sobe, T., Sa'ed, J. A., Rayan, A. A., Lynch, E. D., Lee, M. K., Avraham, K. B., King, M.-C., Kanaan, M. Mutations in a novel isoform of TRIOBP that encodes a filamentous-acting binding protein are responsible for DFNB28 recessive nonsyndromic hearing loss. Am. J. Hum. Genet. 78: 144-152, 2006. [PubMed: 16385458] [Full Text: https://doi.org/10.1086/499495]