The 10 different genes associated with the deaf/blind disorder, Usher syndrome, encode a number of structurally and functionally distinct proteins, most expressed as multiple isoforms/protein variants. Functional characterization of these proteins suggests a role in stereocilia development in cochlear hair cells, likely owing to adhesive interactions in hair bundles. In mature hair cells, homodimers of the Usher cadherins, cadherin 23 and protocadherin 15, interact to form a structural fiber, the tip link, and the linkages that anchor the taller stereocilia's actin cytoskeleton core to the shorter adjacent stereocilia and the elusive mechanotransduction channels, explaining the deafness phenotype when these molecular interactions are perturbed. The conundrum is that photoreceptors lack a synonymous mechanotransduction apparatus, and so a common theory for Usher protein function in the two neurosensory cell types affected in Usher syndrome is lacking. Recent evidence linking photoreceptor cell dysfunction in the shaker 1 mouse model for Usher syndrome to light-induced protein translocation defects, combined with localization of an Usher protein interactome at the periciliary region of the photoreceptors suggests Usher proteins might regulate protein trafficking between the inner and outer segments of photoreceptors. A distinct Usher protein complex is trafficked to the ribbon synapses of hair cells, and synaptic defects have been reported in Usher mutants in both hair cells and photoreceptors. This review aims to clarify what is known about Usher protein function at the synaptic and apical poles of hair cells and photoreceptors and the prospects for identifying a unifying pathobiological mechanism to explain deaf/blindness in Usher syndrome.
Keywords: 4.1 protein, ezrin, radixin, moesin; AMPA; CD; CDH23; CIB2; Cochlear hair cell; EAR; FERM; GST; LTLD; Mechanotransduction; MyTH4; PCDH15; PDZ; PDZ domain containing 7; PDZD7; Photoreceptor; RP; RPE; RPE65; Retinitis pigmentosa; Ribbon synapse; SNAP25; SNARE; TMHS; USH; UTLD; Usher syndrome; VLGR1; cadherin 23; calcium integrin binging protein 2; cytoplasmic domain; deaf circler; dfcr; epilepsy associated repeat; glutathione S-transferase; lower tip link density; myosin tail homology 4; post synaptic density protein (PSD95), Drosophila disk large tumor suppressor (Dlg1), Zonula occludens-1 protein (zo-1); protocadherin 15; retinal pigment epithelium; retinal pigment epithelium-specific 65kDa protein; soluble NSF attachment protein receptor; synaptosomal-associated protein 25; tetraspan membrane protein of hair cell stereocilia; upper tip link density; very large G-coupled protein receptor type 1; α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid.
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