The Structural Function of GIPC3 in the Inner Ear and its Role in Hearing Loss

The GIPC family of proteins function as key molecular scaffolds that are critical in the physical integrating of multiple steps of signaling from receptor activation to intracellular signaling. GIPC3 plays an essential role in the auditory system with mutations in GIPC3 causing inherited nonsyndromic hearing loss. Despite this unique and crucial function in the auditory system, the molecular function of GIPC3, and why mutations in the GIPC3 gene leads to hearing loss, is unknown. We will define the structural basis for GIPC3 function, and the mechanism(s) by which the eleven reported patient mutations lead to inherited hearing loss in physiological setting. Defining the structure and functional interactions of GIPC3, and the molecular basis for dysfunction, requires an integrated structural, biochemical, and physiological approach that form the heart of our proposed collaborative work. We propose three specific aims. In Aim 1, we will establish the biochemical and cellular mechanism of GIPC3 in the inner ear. Aim 2 will focus on understanding the basis for the spectrum of GIPC3-mediated of hearing loss severity. Finally, in Aim 3 we will define the physiology of GIPC3 dysfunction in hearing loss. Taken together, these studies represent a concerted series of steps towards our long-term goal of understanding the physical mechanisms underlying the role GIPC3 in normal physiological function, and will inform ongoing efforts to understand and ameliorate GIPC3 dysfunction in disease.