Sequence similarity between stereocilin and otoancorin points to a unified mechanism for mechanotransduction in the mammalian inner ear

Abstract

Background: Interaction between hair cells and acellular gels of the mammalian inner ear, the tectorial and otoconial membranes, is crucial for mechanoreception. Recently, otoancorin was suggested to be a mediator of gel attachment to nonsensory cells, but the molecular components of the interface between gels and sensory cells remain to be identified.

Hypothesis: We report that the inner ear protein stereocilin is related in sequence to otoancorin and, based on its localisation and predicted GPI-anchoring, may mediate attachment of the tectorial and otoconial membranes to sensory hair bundles.

Testing: It is expected that antibodies directed against stereocilin would specifically label sites of contact between sensory hair cells and tectorial/otoconial membranes of the inner ear.

Implications: Our findings support a unified molecular mechanism for mechanotransduction, with stereocilin and otoancorin defining a new protein family responsible for the attachment of acellular gels to both sensory and nonsensory cells of the inner ear.

Figure 1

Multiple sequence alignment of stereocilin, otoancorin and mesothelin. Regions of homology are boxed, residues identical in more than 60% of the sequences are shaded in yellow and 4 cysteine residues conserved in all sequences are indicated by red dots. AAL35321, mouse stereocilin (1809 aa); XP_090942, human stereocilin (1778 aa); STRC_FURU, Fugu rubripes stereocilin (see below); NP_647471, mouse otoancorin (1137 aa); DAA00022, human otoancorin (1153 aa); NP_061345, mouse mesothelin (625 aa); NP_113846, rat mesothelin (625 aa); AAH03512, human mesothelin (621 aa). A gene encoding the putative Fugu fish homologue of stereocilin was identified by a BLAST [18] search of Fugu assembly release 2 (17.05.02) [19] with mouse stereocilin, matching sequences within scaffold 1525 (E-value 8.2^e-58). GENSCAN [20] analysis of the genomic DNA was combined to local sequence alignments to known stereocilin sequences to yield a putative Fugu stereocilin homologue of 1994 amino acids, including an N-terminal signal peptide sequence and a predicted C-terminal GPI-anchor attachment site. STRC mutations resulting in truncation of stereocilin at amino acid positions preceding the start of the alignment with mesothelin were identified in human families affected by non-syndromal sensorineural deafness linked to locus DFNB16 [11].