Table 2.
Degeneration stages as defined in Figure 1 in the adult cochlea of mutant mouse models.
| Degeneration stage in adult | Gene name | Main cellular expression sites in the cochlea | Major morphological findings in the cochlea of mutant mice |
|---|---|---|---|
| Stage I* | STRC | An extracellular matrix protein that attaches the tallest stereocilia of the OHC to the tectorial membrane | Tip links are still present, however horizontal top connectors are absent from the hair bundles of the OHCs. The distal ends of the stereocilia are more loosely connected than in wild-type mice (Verpy et al., 2011). |
| Stage I | CLDN11 | Tight junction protein of SCs and HCs (Gow et al., 2004; Hilgert et al., 2009a) | In mice, mutations in Cldn11 do not change the EP. Both OHC and IHCs are intact for the first few months, then degeneration starts slowly in OHCS, followed by IHC degeneration (Gow et al., 2004; Hilgert et al., 2009a). |
| Stage I | TECTA | non-collagenous component of the tectorial membrane (TM) | TM is detached completely from the organ of Corti (Legan et al., 2014). |
| Stage I or II | OTOF | At the synaptic cleft of the IHC (Egilmez and Kalcioglu, 2016) | Defective synaptic vesicle fusion at the IHC ribbon synapse. OHCs are less affected. In Otof null mice, OHC function is preserved while IHC synaptic exocytosis is abolished (Hilgert et al., 2009b). Central auditory neurons are also affected (Yasunaga et al., 1999). |
| Stage I or II | PJVK | In HCs and SGNs | OHC degeneration and followed by delayed loss of IHCs (Delmaghani et al., 2006). |
| Stage II | KCNQ4 | IHCs, OHCs and SGNs | Mainly manifest as OHC degeneration and loss of function (Boettger et al., 2002). |
| Possibly at stage II | GJB6 | SCs, but not expressed by HCs. | Co-assembled with the Gjb2. Comparing to the Gjb2 null, Gjb6 null show delayed time course of degeneration starting from OHCS (Sun et al., 2009). Severe degeneration of SCs & HCS in the middle & basal turns eventually is observed after a few months in mice. |
| Stage III or IV | GJB2 | SCs, not expressed by HCs | The cochlea is not fully developed. Severe degeneration of all types of cochlear cells in the middle & basal turns at onset of hearing in mice. HCs and SCs survive in the apical turn, but with immature functional features (Wang et al., 2009). |
| Stage III | TMC1 | In both IHCs, OHCs and neurosensory epithelia of the vestibular organs. | Hair cell degeneration, and secondary degeneration of other cochlear cells, staring from the onset of hearing in mice (Kawashima et al., 2011; Pan et al., 2013). |
| Stage III | CDH23 | A main component of the tip link | Hair cell degeneration, and secondary degeneration of other cochlear cells early in cochlear development in mice (Di Palma et al., 2001). |
| Stage III | USH1C | In stereocilia, the cuticular plate, the lateral plasma membrane and synapses. | Hair cell degeneration, and secondary degeneration of other cochlear cells early in cochlear development in mice (Hilgert et al., 2009a; Lentz et al., 2013). |
| Stage III | MYO3A | at stereocilia tips, also found further down the shaft of the stereocilia | Hair cell degeneration, and secondary degeneration of other cochlear cells (Hilgert et al., 2009a). |
| Stage III | MYO6 | in the cuticular plate | Hair cell degeneration, and secondary degeneration of other cochlear cells early in cochlear development in mice (Friedman et al., 1999). |
| Stage III | MYO7A | Mainly in the stereocilia but also along the lateral membrane of the HCs, in the cuticular plate and in the synaptic region. | Malformation of hair cell stereocilia and progressive degeneration of HCs in the organ of Corti early in development stages (Zuo, 2002). |
| Stage III or IV | SLC26A4 | In the apical membrane of outer sulcus and spiral prominence epithelial cells that border the endolymph, in the SG and in SCs | Degeneration of all types of cells in the cochlea, starting from embryonic stage (Wangemann et al., 2007). |
| Stage III or IV | KCNQ1 | Apical membrane of the marginal cells of the stria vascularis. | Collapse of Reissner's membrane, degeneration of IHC, OHCs and other cells in the organ of Corti, degeneration of cells in the SV (Casimiro et al., 2001; Chang et al., 2015b). |
| Stage III (possibly II) | ATP6V1B1 | In the epithelial cells of the endolymphatic sac and duct, and in the interdental cell layer of the cochlear spiral limbus | Enlargement of endolymphatic sac and duct. Some HCs and SGNs are preserved. OHCs were generally absent in the cochlear base, but present to a variable extent in the apex (Karet et al., 1999). |
Representative examples are given here due to space and formatting limitations. More complete and detailed information of deafness genes is provided in Supplemental Table 2.
*
Definition of degeneration stages are given in the Figure 2. Our discussions suggest that the chance of success of cochlear gene therapy is greatly affected by the severity of cochlear degeneration. Only disease progression with less severe stages (stages I&II, given in shaded rows) appears to be amenable to cochlear gene therapies for hearing restoration.