1.A.116.  The Transmembrane Inner Ear (TMIE) Family

The circling (cir/cir) mouse is a spontaneous model of deafness due to deletion of a 40-kb genomic region that includes the transmembrane inner ear (tmie) gene. In addition to being deaf, cir/cir mice exhibit abnormal behaviors including circling and hyperactivity. Park et al. 2013 investigated differences between 3-day old (that is, before hair-cell degeneration) cir/cir and phenotypically normal ( /cir) mice and the reason underlying the degeneration of the inner ear structure of cir/cir mice. To this end, they used gentamicin, gentamicin-Texas red conjugate, and FM1-43 to investigate mechanotransducer channel activity in the hair cells of cir/cir mice.  These compounds are presumed to enter hair cells through the mechanotransducer channel. Although the structure of the inner ear of /cir mice was equivalent to that of cir/cir mice, the hair cells of cir/cir mice (unlike /cir) did not take up gentamicin, gentamicin-Texas red conjugate, or FM1-43. These findings suggest that hair cells in cir/cir mice demonstrate abnormal maturation and mechanotransduction. In addition, the results indicated that tmie is required for maturation and maintenance of hair cells.

Mechanotransduction channels in hair cells are gated by tip links.  Zhao et al. 2014 showed that the transmembrane inner ear protein, TMIE, forms a ternary complex with the tip-link component PCDH15 and its binding partner TMHS/LHFPL5. Alternative splicing of the PCDH15 cytoplasmic domain regulates formation of this ternary complex. Transducer currents are abolished by a homozygous Tmie-null mutation, and subtle Tmie mutations that disrupt interactions between TMIE and tip links affect transduction, suggesting that TMIE is an essential component of the hair cell's mechanotransduction machinery that functionally couples the tip link to the transduction channel. The multisubunit composition of the transduction complex and the regulation of complex assembly by alternative splicing is likely critical for regulating channel properties in different hair cells and along the cochlea's tonotopic axis (Zhao et al. 2014).

Mutations in transmembrane inner ear (TMIE) cause deafness in humans due to an involvement in the mechano-electrical transduction (MET) (TC# 1.A.17.4.13) complex in sensory hair cells. In tmie zebrafish mutants, Pacentine and Nicolson 2019 showed that GFP-tagged Tmc1 and Tmc2b, subunits of the MET channel, fail to target to the hair bundle, but overexpression of Tmie strongly enhances the targeting of Tmc1-GFP and Tmc2b-GFP to stereocilia. The extracellular region and transmembrane domain of TMIE are required for both mechanosensitivity and Tmc2b-GFP expression in the bundles. Thus, Tmie's role in sensory hair cells is to target and stabilize Tmc channel subunits to the site of MET (Pacentine and Nicolson 2019).