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Other entities represented in this entry:
HGNC Approved Gene Symbol: SLC26A5
Cytogenetic location: 7q22.1 Genomic coordinates (GRCh38): 7:103,352,730-103,446,207 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q22.1 | ?Deafness, autosomal recessive 61 | 613865 | Autosomal recessive | 3 |
Prestin is the motor protein of cochlear outer hair cells (Zheng et al., 2000).
The outer and inner hair cells of the mammalian cochlea perform different functions. In response to changes in membrane potential, the cylindrical outer hair cell rapidly alters its length and stiffness. These mechanical changes, driven by putative molecular motors, are assumed to produce amplification of vibrations in the cochlea that are transduced by inner hair cells. Inasmuch as the most distinguishing feature of this molecular motor is its speed, Zheng et al. (2000) designated it 'prestin' from the musical notation 'presto.' They applied a suppression subtractive hybridization PCR procedure to amplify and enrich the outer hair cell cDNA pool for uniquely expressed gene products from gerbil. Pres fragments in the PCR subtracted library were abundant, at greater than 10% of 487 differentially expressed clones, and showed consistent differential hybridization with outer hair cell- and inner hair cell-derived probes. The full-length clone of gerbil Pres was isolated from an adult gerbil cochlea library. A computer search with the gerbil Pres sequence revealed that about one-third of the human PRES gene had been sequenced as part of the human chromosome 7 effort (GenBank AC005064). The amino acid homology between human and gerbil prestin deduced from the genomic sequence of the first 6 exons is 98%. Prestin has highest homology to members of the family of sulfate/anion transport proteins including pendrin (605646) and DRA (downregulated in adenoma; 126650). Prestin is approximately 40% homologous to pendrin. Northern blot analysis with gerbil mRNA did not detect expression in liver, lung, brain, spleen, ovary, kidney, muscle, or heart. Virtual Northern dot-blot analysis using cDNA prepared from inner hair cells, outer hair cells, mature and newborn organs of Corti, and thyroid revealed expression only in mature outer hair cells and 20-day-old organs of Corti.
Liu et al. (2003) cloned and characterized 4 splicing isoforms of the human SLC26A5 gene, designated SLC26A5A-D, that encode deduced proteins of 744, 685, 516, and 335 amino acids, respectively. SLC26A5A-C contain the complete set of 12 predicted transmembrane domains, whereas SLC26A5D has only 7 of the predicted transmembrane domains. All 4 isoforms preserve the sulfate transport motif, but not the STAS domain. SLC26A5A was the most abundant, adult form of prestin in the cochlea, and the other 3 isoforms were expressed at a lower level and appeared to show different expression during development.
Liu et al. (2003) determined that the SLC26A5 gene contains 21 exons. SLC26A5B-D all share the same terminal 3-prime exon, but differ in their intervening cDNA sequences. SLC26A5A-B share the majority of the sequence and differ only at the terminal 3-prime exon. A consensus polyadenylation signal is present in the 3-prime UTR of SLC26A5B-D, but not in the 3-prime UTR of SLC26A5A.
Liu et al. (2003) mapped the SLC26A5 gene to chromosome 7q22.1.
Zheng et al. (2000) elicited voltage-induced shape changes in cultured human kidney cells that expressed prestin. The mechanical response of outer hair cells to voltage change was accompanied by a 'gating current,' which was manifested as nonlinear capacitance. Zheng et al. (2000) also demonstrated this nonlinear capacitance in transfected kidney cells. They concluded that prestin is the motor protein of cochlear outer hair cells.
Oliver et al. (2001) demonstrated that voltage sensitivity is conferred to prestin by the intracellular anions chloride and bicarbonate. Removal of these anions abolished fast voltage-dependent motility, as well as the characteristic nonlinear charge movement ('gating currents') driving the underlying structural rearrangements of the protein. Oliver et al. (2001) suggested a model in which anions act as extrinsic voltage sensors, which bind to the prestin molecule and thus trigger the conformational changes required for the motility of outer hair cells.
The most impressive property of outer hair cells (OHCs) in the cochlea is their ability to change their length at high acoustic frequencies, thus providing the exquisite sensitivity and frequency-resolving capacity of the mammalian hearing organ. Prestin appears to be the OHC motor molecule. Homology searches of the coding region of the prestin gene allowed the identification of a thyroid hormone response element (TRE) in the first intron upstream of the prestin ATG start codon (Weber et al., 2002). Prestin(TRE) bound thyroid hormone receptors (THRA, 190120; TRHB, 190160) as a monomer or presumptive heterodimer and mediated a triiodothyronine-dependent transactivation of a heterologous promoter in response to triiodothyronine receptors alpha and beta. Retinoid X receptor-alpha (180245) had an additive effect. Expression of prestin mRNA and prestin protein was reduced strongly in the absence of thyroid hormone. On the basis of these data, Weber et al. (2002) suggested thyroid hormone as a first transcriptional regulator of the motor protein prestin and as a direct or indirect modulator of subcellular prestin distribution.
Johnson et al. (2011) studied organs of Corti isolated from young rats and gerbils. They found that, at physiologic endolymphatic calcium concentrations, approximately half of the mechanotransducer channels were opened at rest, depolarizing the membrane potential to near -40 mV. This resting potential appeared similar to the membrane potential at which prestin has steepest voltage sensitivity. Johnson et al. (2011) concluded that minimal time constant filtering ensures optimal prestin activation.
Using negatively stained electron microscopy and single-particle analysis, Mio et al. (2008) determined the 3-dimensional structure of recombinant full-length rat prestin at 2-nanomolar resolution. Prestin formed tetramers that had an overall bullet shape, with a relatively small extracellular N-terminal end and a large squared cytoplasmic C-terminal domain. Slice images revealed an inner cavity of sparse density. Mio et al. (2008) noted that, although prestin belongs to a family of anion transporters, it does not transport ions across the plasma membrane. Instead, prestin changes its structure by voltage-dependent translocation of anions within the molecule, perhaps via the low-density space within the prestin tetramer.
Minor et al. (2009) studied 56 hearing loss patients and 212 controls and identified 23 sequence variations, 21 of which were located in noncoding regions of SLC26A5. Two coding sequence variations, S434S and I663V, were observed only in patients. In silico analysis of the I663V variant suggested that it might be benign.
In a study of 58 subjects from 15 unrelated Japanese families with hearing loss, Mutai et al. (2013) identified 2 sisters who were compound heterozygous for mutations in the SLC26A5 gene: a missense mutation (R130S; 604943.0002) inherited from their mother, and a nonsense mutation (W70X; 604943.0003) inherited from their father. The mutations were not found in the dbSNP (build 135), 1000 Genomes Project, or Exome Variant Server databases, and the R130S mutation was not found in 192 Japanese controls.
Liberman et al. (2002) created mice deficient in prestin by targeted disruption. Homozygous mutant mice had a loss of outer hair cell electromotility in vitro and a 40-60 dB loss of cochlear sensitivity in vivo, without disruption of mechanoelectrical transduction in outer hair cells. In heterozygotes, electromotility was halved and there was a 2-fold (about 6 dB) increase in cochlear thresholds. Liberman et al. (2002) concluded that prestin is the motor protein required for electromotility, that there is a simple and direct coupling between electromotility and cochlear amplification, and that there is no need to invoke additional active processes to explain cochlear sensitivity in the mammalian ear.
Using a knockin mouse model, Homma et al. (2013) showed that substitution of val499 with gly (V499G) drastically altered the electromotility of mouse prestin. V499 was predicted to reside near the C-terminal end of the last transmembrane segment, immediately preceding the intracellular C-terminal domain. V499G mutant prestin was targeted appropriately to membranes and formed heterotetramers with wildtype prestin. The motor function of prestin was not affected by multimer formation, suggesting functional independence of prestin subunits within multimers.
By studying the phylogenetic history and molecular evolution of the prestin gene in mammals, Li et al. (2008) found evidence that prestin has undergone positive selection associated with the evolution of high frequency hearing in echolocating bats. Over 80% of the sites under positive selection occur in functionally important regions, including those involved in voltage sensing, sulfate transport, and protein targeting.
This variant, formerly titled DEAFNESS, AUTOSOMAL RECESSIVE 61, has been reclassified based on the findings of Shearer et al. (2014). Based on allele frequency in 8,595 controls from 12 populations (maximum minor allele frequency = 0.0156), Shearer et al. (2014) recategorized the c.-53-2A-G variant in the SLC26A5 gene as benign.
In 2 of 220 Caucasian probands with nonsyndromic deafness (DFNB61; 613865), Liu et al. (2003) identified a homozygous A-to-G transition at position -2 in intron 2 of the PRES gene, resulting in aberrant splicing. One of the 2 probands was born to nonconsanguineous parents in a simplex sibship, whereas the other was born to consanguineous parents in a multiplex sibship in which 2 sibs were also reported as deaf but who were unavailable for testing. In addition, heterozygosity for this mutation was observed in 7 (3%) of the 220 probands, suggesting the possibility of semidominant influence of the mutation in causing hearing loss. The mutation was not found in 250 Caucasian control subjects. No mutation in the SLC26A5 gene was found in 150 deaf probands from other ethnic backgrounds, suggesting an association with a specific ethnic background.
In a study of 84 hearing-impaired individuals and 246 Caucasian and Hispanic controls, Tang et al. (2005) identified 4 hearing-impaired individuals and 4 controls who were heterozygous for the IVS2-2A-G mutation. They did not find the mutation in homozygous state in any of the 330 subjects. Tang et al. (2005) stated that the allele frequency of the IVS2-2A-G variant was not statistically significantly different between cases and controls, thus challenging whether it was associated with hearing loss.
In 2 Japanese sisters, aged 6 and 9 years, with moderate to severe hearing loss (family 3), Mutai et al. (2013) identified compound heterozygosity for 2 mutations in the SLC26A5 gene: a c.390A-C transversion, resulting in an arg130-to-ser (R130S) substitution, inherited from their mother, and a c.209G-A transition, resulting in a trp70-to-ter (W70X; 604943.0003) substitution, inherited from their father. These mutations were not found in the dbSNP (build 135), 1000 Genomes Project, or NHLBI Exome Sequencing Project databases. The c.390A-C mutation was not found in 192 Japanese controls.
For discussion of the trp70-to-ter (W70X) mutation in the SLC26A5 gene that was found in compound heterozygous state in Japanese sisters with autosomal recessive hearing loss (DFNB61; 613865) by Mutai et al. (2013), see 604943.0002.
Homma, K., Duan, C., Zheng, J., Cheatham, M. A., Dallos, P. The V499G/Y501H mutation impairs fast motor kinetics of prestin and has significance for defining functional independence of individual prestin subunits. J. Biol. Chem. 288: 2452-2463, 2013. [PubMed: 23212912] [Full Text: https://doi.org/10.1074/jbc.M112.411579]
Johnson, S. L., Beurg, M., Marcotti, W., Fettiplace, R. Prestin-driven cochlear amplification is not limited by the outer hair cell membrane time constant. Neuron 70: 1143-1154, 2011. [PubMed: 21689600] [Full Text: https://doi.org/10.1016/j.neuron.2011.04.024]
Li, G., Wang, J., Rossiter, S. J., Jones, G., Cotton, J. A., Zhang, S. The hearing gene Prestin reunites echolocating bats. Proc. Nat. Acad. Sci. 105: 13959-13964, 2008. [PubMed: 18776049] [Full Text: https://doi.org/10.1073/pnas.0802097105]
Liberman, M. C., Gao, J., He, D. Z. Z., Wu, X., Jia, S., Zuo, J. Prestin is required for electromotility of the outer hair cell and for the cochlear amplifier. Nature 419: 300-304, 2002. [PubMed: 12239568] [Full Text: https://doi.org/10.1038/nature01059]
Liu, X. Z., Ouyang, X. M., Xia, X. J., Zheng, J., Pandya, A., Li, F., Du, L. L., Welch, K. O., Petit, C., Smith, R. J. H., Webb, B. T., Yan, D., Arnos, K. S., Corey, D., Dallos, P., Nance, W. E., Chen, Z. Y. Prestin, a cochlear motor protein, is defective in non-syndromic hearing loss. Hum. Molec. Genet. 12: 1155-1162, 2003. [PubMed: 12719379] [Full Text: https://doi.org/10.1093/hmg/ddg127]
Minor, J. S., Tang, H.-Y., Pereira, F. A., Alford, R. L. DNA sequence analysis of SLC26A5, encoding prestin, in a patient-control cohort: identification of fourteen novel DNA sequence variations. PLoS One 4: e5762, 2009. Note: Electronic Article. [PubMed: 19492055] [Full Text: https://doi.org/10.1371/journal.pone.0005762]
Mio, K., Kubo, Y., Ogura, T., Yamamoto, T., Arisaka, F., Sato, C. The motor protein prestin is a bullet-shaped molecule with inner cavities. J. Biol. Chem. 283: 1137-1145, 2008. [PubMed: 17998209] [Full Text: https://doi.org/10.1074/jbc.M702681200]
Mutai, H., Suzuki, N., Shimizu, A., Torii, C., Namba, K., Morimoto, N., Kudoh, J., Kaga, K., Kosaki, K., Matsunaga, T. Diverse spectrum of rare deafness genes underlies early-childhood hearing loss in Japanese patients: a cross-sectional, multi-center next-generation sequencing study. Orphanet J. Rare Dis. 8: 172, 2013. Note: Electronic Article. [PubMed: 24164807] [Full Text: https://doi.org/10.1186/1750-1172-8-172]
Oliver, D., He, D. Z. Z., Klocker, N., Ludwig, J., Schulte, U., Waldegger, S., Ruppersberg, J. P., Dallos, P., Fakler, B. Intracellular anions as the voltage sensor of prestin, the outer hair cell motor protein. Science 292: 2340-2343, 2001. [PubMed: 11423665] [Full Text: https://doi.org/10.1126/science.1060939]
Shearer, A. E., Eppsteiner, R. W., Booth, K. T., Ephraim, S. S., Gurrola, J., II, Simpson, A., Black-Ziegelbein, E. A., Joshi, S., Ravi, H., Giuffre, A. C., Happe, S., Hildebrand, M. S., and 20 others. Utilizing ethnic-specific differences in minor allele frequency to recategorize reported pathogenic deafness variants. Am. J. Hum. Genet. 95: 445-453, 2014. [PubMed: 25262649] [Full Text: https://doi.org/10.1016/j.ajhg.2014.09.001]
Tang, H.-Y., Xia, A., Oghalai, J. S., Pereira, F. A., Alford, R. L. High frequency of the IVS2-2A-G DNA sequence variation in SLC26A5, encoding the cochlear motor protein prestin, precludes its involvement in hereditary hearing loss. BMC Med. Genet. 6: 30, 2005. Note: Electronic Article. [PubMed: 16086836] [Full Text: https://doi.org/10.1186/1471-2350-6-30]
Weber, T., Zimmermann, U., Winter, H., Mack, A., Kopschall, I., Rohbock, K., Zenner, H.-P., Knipper, M. Thyroid hormone is a critical determinant for the regulation of the cochlear motor protein prestin. Proc. Nat. Acad. Sci. 99: 2901-2906, 2002. Note: Erratum: Proc. Nat. Acad. Sci. 99: 7809 only, 2002. [PubMed: 11867734] [Full Text: https://doi.org/10.1073/pnas.052609899]
Zheng, J., Shen, W., He, D. Z. Z., Long, K. B., Madison, L. D., Dallos, P. Prestin is the motor protein of cochlear outer hair cells. Nature 405: 149-155, 2000. [PubMed: 10821263] [Full Text: https://doi.org/10.1038/35012009]