HGNC Approved Gene Symbol: OTOA
Cytogenetic location: 16p12.2 Genomic coordinates (GRCh38): 16:21,663,968-21,760,729 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16p12.2 | Deafness, autosomal recessive 22 | 607039 | Autosomal recessive | 3 |
The OTOA gene encodes otoancorin, which belongs to a group of noncollagenous glycoproteins of the acellular gels of the inner ear that have been described in mammals. Examples include alpha-tectorin (602574), beta-tectorin (602653), and otogelin (OTOG; 604487), all of which are unique to the inner ear (Zwaenepoel et al., 2002).
Zwaenepoel et al. (2002) reported the first example of a protein, otoancorin (OTOA), specifically located at the interface between the apical surface of the sensory epithelia and their overlying acellular gels, and also entirely specific for the inner ear. By searching a subtracted cDNA library prepared from sensory epithelia of the mouse vestibular apparatus, followed by searching sequence databases, they obtained cDNAs encoding mouse and human OTOA. The predicted 1,153-amino acid human protein is 77% identical to the mouse protein. Mouse Otoa has a signal peptide, 11 potential N-glycosylation sites, and a C-terminal sequence characteristic of GPI-linked membrane-bound proteins. RT-PCR analysis detected expression of mouse Otoa only in the inner ear.
By sequence analysis using a gene-prediction program, Zwaenepoel et al. (2002) determined that the OTOA gene has 28 exons spanning approximately 82 kb.
By genomic sequence analysis, Zwaenepoel et al. (2002) mapped the OTOA gene between markers D16S3046 and D16S412 on chromosome 16p12.2.
Since the mouse Otoa gene is expressed only in the inner ear, Zwaenepoel et al. (2002) considered the human gene to be an attractive candidate gene for isolated deafness. They searched a collection of 200 large affected families to determine whether the deafness locus in any mapped to 16p12.2. In a consanguineous Palestinian family, the moderate to severe prelingual sensorineural recessive deafness was shown to segregate with a locus, termed DFNB22 (607039), on chromosome 16p13.1-q11.2. Zwaenepoel et al. (2002) identified a T-to-C transition at the exon 12/intron 12 junction of the OTOA gene (607038.0001) in the homozygous state in 1 affected child of this family. The mutation was found to cosegregate with the hearing impairment in this kindred and was not detected in 417 Jordanian, Lebanese, Palestinian, and Jewish (mainly Sephardic and Yemenite) individuals with normal hearing.
In affected sibs from a consanguineous Palestinian family with autosomal recessive prelingual deafness, Shahin et al. (2010) identified a homozygous 500-kb deletion that resulted in complete deletion of the OTOA gene (607038.0002). The deletion was flanked by segmental duplications at chromosome 16q, suggesting nonallelic homologous recombination as the mechanism. The deletion was observed in the heterozygous state in 3 (1.0%) of 288 unrelated Palestinian controls.
In affected members of 3 consanguineous Pakistani families with DFNB22, Lee et al. (2013) identified 2 different homozygous missense mutations in the OTOA gene (G451D, 607038.0003 and P627S, 608038.0004). Functional studies of the variants were not performed, but both mutations were predicted to interrupt the superhelical structure of OTOA, which would result in an inability of otoancorin to stabilize the tectorial members on top of sensory hair cells in the inner ear. The patients had prelingual onset of severe to profound hearing loss affecting all frequencies.
In a large consanguineous Palestinian family, Zwaenepoel et al. (2002) found that moderate to severe prelingual sensorineural recessive deafness (DFNB22; 607039) segregated with a mutation in the OTOA gene, a T-to-C transition at the exon 12/intron 12 junction in the homozygous state. The IVS12+2T-C mutation affected the invariant T of the donor splice site GT dinucleotide and was expected to lead to aberrant splicing, such as exon 12 skipping, resulting in an in-frame deletion of 72 amino acids, or the use of a cryptic site.
In affected sibs from a consanguineous Palestinian family with autosomal recessive prelingual deafness (DFNB22; 607039), Shahin et al. (2010) identified a homozygous 500-kb deletion that resulted in complete deletion of the OTOA gene. The deletion was flanked by segmental duplications at chromosome 16q, suggesting nonallelic homologous recombination as the mechanism. The deletion was observed in the heterozygous state in 3 (1.0%) of 288 unrelated Palestinian controls.
In 4 members of a large consanguineous Pakistani family with DFNB22 (607039), Lee et al. (2013) identified a homozygous c.1352G-A transition in the OTOA gene, resulting in a gly451-to-asp (G451D) substitution at a highly conserved residue within a buried alpha-helical segment. The mutation, which was found by linkage analysis followed by candidate gene sequencing, was not present in 670 control chromosomes. Functional studies of the variant were not performed, but the mutation was predicted to interrupt the superhelical structure of OTOA. The patients had prelingual onset of severe to profound hearing loss affecting all frequencies.
In 4 patients from 2 unrelated consanguineous Pakistani families with DFNB22 (607039), Lee et al. (2013) identified a homozygous c.1879C-T transition in the OTOA gene, resulting in a pro627-to-ser (P627S) substitution at a highly conserved residue within an exposed coil region as a domain linker. The mutation, which was found by linkage analysis followed by candidate gene sequencing, was not present in 670 control chromosomes. Functional studies of the variant were not performed, but the mutation was predicted to interrupt the superhelical structure of OTOA. The patients had prelingual onset of severe to profound hearing loss affecting all frequencies.
Lee, K., Chiu, I., Santos-Cortez, R. L. P., Basit, S., Khan, S., Azeem, Z., Andrade, P. B., Kim, S. S., Ahmad, W., Leal, S. M. Novel OTOA mutations cause autosomal recessive non-syndromic hearing impairment in Pakistani families. (Letter) Clin. Genet. 84: 294-296, 2013. [PubMed: 23173898] [Full Text: https://doi.org/10.1111/cge.12047]
Shahin, H., Walsh, T., Rayyan, A. A., Lee, M. K., Higgins, J., Dickel, D., Lewis, K., Thompson, J., Baker, C., Nord, A. S., Stray, S., Gurwitz, D., Avraham, K. B., King, M.-C., Kanaan, M. Five novel loci for inherited hearing loss mapped by SNP-based homozygosity profiles in Palestinian families. Europ. J. Hum. Genet. 18: 407-413, 2010. [PubMed: 19888295] [Full Text: https://doi.org/10.1038/ejhg.2009.190]
Zwaenepoel, I., Mustapha, M., Leibovici, M., Verpy, E., Goodyear, R., Liu, X. Z., Nouaille, S., Nance, W. E., Kanaan, M., Avraham, K. B., Tekaia, F., Loiselet, J., Lathrop, M., Richardson, G., Petit, C. Otoancorin, an inner ear protein restricted to the interface between the apical surface of sensory epithelia and their overlying acellular gels, is defective in autosomal recessive deafness DFNB22. Proc. Nat. Acad. Sci. 99: 6240-6245, 2002. [PubMed: 11972037] [Full Text: https://doi.org/10.1073/pnas.082515999]