The long term goal of this research is to understand cellular mechanisms in photoreceptor cells, especially those involved in turnover of the phototransductive membrane. The proposed plan is to focus on understanding the role of myosin VIIa in the retina. Myosin VIIa is the product of the gene defective in Usher syndrome type 1B, which accounts for about 50 percent of all Usher syndrome cases. Usher syndrome is the most common inherited blindness-deafness disorder, and accounts for about 17 percent of all cases of retinitis pigmentosa. Preliminary studies suggest a role for myosin VIIa in the turnover of phototransductive membrane. The proposed studies will use shaker-1 mice, which are mutant for myosin VIIa, to study the in vivo retinal function of myosin VIIa. In addition, purified myosin VIIa will be used to investigate protein structure and function in vitro. In studies leading up to those proposed, we localized myosin VIIa in the connecting cilia of the photoreceptor cells and, as others had found, in the apical processes of the retinal pigment epithelium (RPE). Here, the photoreceptor cells and the RPE cells will be examined in different alleles of shaker-1 mice to determine the cellular phenotypes resulting from mutant myosin VIIa. To complement the studies on shaker-1 mice, the quaternary structure and biochemical properties of myosin VIIa will be investigated. These studies will include tests of the capabilities of myosin VIIa. Thus they will test the fit of hypotheses proposed for the retinal function of myosin VIIa from the studies on shaker-1 mice. In this respect, questions to be addressed include: does the protein exhibit myosin-like motor function, and how does it interact with suggested cargo? The proposed research is pertinent to: (1) The structure and function of an unconventional myosin; (2) The mystery of how opsin is delivered to the outer segment; and (3) Blindness in Usher syndrome 1B.
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