Roles and Interactions of Three USH1 Proteins in the Retina and Inner Ear

Abstract

Abstract: : Purpose: Usher syndrome type 1 (Usher–1) is a recessive disorder, involving profound deafness, vestibular dysfunction and progressive retinal degeneration. It can be caused by mutations in any one of seven known genes. We have focused on three of the identified Usher–1 proteins: myosin VIIa (MYO7A), cadherin 23 (CDH23) and harmonin (USH1C, a PDZ domain protein). We are interested in the retinal and cochlear function of these proteins and whether they interact in these tissues. Methods: We generated specific antibodies against MYO7A, CDH23 and USH1C, and we established stocks of mice carrying mutations in the three genes. We have studied the precise localization of these proteins in the retina and inner ear using electron microscopy and biochemical techniques. Results: All three proteins are present in the cochlear hair cells, and are independently required for normal hair cell development. In mature hair cells, we have identified CDH23 as a component of the stereociliary tip link, and thus a central element of mechanotransduction. CDH23 is also localized in the kinocilium of hair cells and the connecting cilium of photoreceptor cells, as described previously for MYO7A. USH1C was detected in the sterocilia but not in the kinocilium of hair cells. In the retina, USH1C was localized in the rod synapses and photoreceptor inner and outer segments, but not in the cilium. Conclusions: These results indicate that CDH23 and MYO7A may interact in the cilia of retinal photoreceptors and cochlear hair cells, whereas USH1C, although a potential anchoring protein, appears to be absent from these structures.

Keywords: photoreceptors • microscopy: electron microscopy • proteins encoded by disease genes