Problems with balance are a leading cause of death and injury in elderly populations. Degeneration of otoconia is thought to contribute significantly to balance disorders and to the displacement or ectopic formation of otoconia that occur in patients suffering from benign paroxysmal positional vertigo (BPPV). Despite the prevalence of balance disorders, little is known about the molecular mechanisms regulating the development and pathology of the vestibular mechanosensory apparatus. The recent identification of genes expressed in the peripheral vestibular system, their requirement for otoconial development, and the availability of mouse mutants that lack otoconia, allow a biochemical and genetic analysis of this sensory system. This proposal aims to advance our understanding of the molecular mechanisms that regulate the development of otoconia, and to provide insight into pathologic mechanisms that contribute to otoconial degeneration. The ultimate goal of this work is to devise methods to prevent otoconial degeneration, to prevent ectopic crystal formation or even to induce regeneration of otoconia. We have positionally cloned a novel gene (Otopetrin 1, Otop1) that is a member of a novel gene family and that is required for otoconial development in the mouse. The mouse mutants, tilted (tlt) and mergulhador (mlh), both contain distinct missense mutations in Otop1. These mouse mutants specifically lack otoconia but have an apparently normal sensory epithelium. Based on the primary structure of Otop1, its localization in the endoplasmic reticulum and its effect on cellular calcium regulation, we hypothesize that this protein functions as a channel or transporter involved in regulating the contents or function of exocytotie vesicles that may contribute to structures required for the attachment or nucleation of otoconia. We hypothesize that the missense mutations in tit and mlh mice are not null mutations and that Otop1 may have additional in vivo functions not revealed by the phenotype of these mice. We hypothesize that functional redundancy may exist within the Otopetrin gene family. In this proposal, we will identify a biochemical function for Otop1 and determine the mechanism by which the missense mutations in tilted and mergulhador mice alter this biochemical function and disrupt otoconial biosynthesis. We will also generate a mouse knockout for Otop1 to test the hypothesis that Otop1 has additional roles in the normal development or function of the inner ear and of other tissues.
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