Hearing disorders account for the majority of sensory deficit disorders in the United States and affect 1 in 2000 births. Although more than 100 deafness loci are known to exist, fewer than half of the responsible genes have been identified. We have recently identified a mutation in the 5'untranslated region of the diaphanous homolog 3 gene (DIAPH3 in humans, Diap3 in mouse) that leads to increased transcription and delayed onset auditory neuropathy, a form of deafness. A homolog of DIAPH3 has been implicated in another form of deafness as well, but exact roles in the auditory system for the diaphanous-related formins, which interact with actin and microtubules, have not yet been elucidated. We have developed a mouse model of Diap3 overexpression to address this open question. The long-term goal here is to understand the interactions of proteins and molecular pathways important in the mammalian auditory system and how defects in this system lead to hearing loss and/or deafness. The overall objectives of this application are to investigate the developmental expression of Diap3, to characterize a new mouse model of deafness, and to investigate the molecular mechanism responsible for this form of auditory neuropathy. The central hypothesis for the proposed research is that Diap3 overexpression in mice will faithfully model the mechanism of human auditory neuropathy and help elucidate the mechanism of hearing loss, which we postulate is due to actin dysregulation. The rationale for the proposed research is our finding that upregulated DIAPH3 in humans'leads to auditory neuropathy. The central hypothesis will be tested by pursuing two specific aims: 1) Determine the expression profile of Diap3 in wild-type mice and determine the extent of overexpression in our newly developed transgenic mice;and 2) Determine the extent to which Diap3 overexpression affects the auditory system in transgenic mice using classical measures of hearing as well as by investigating differential actin isoform expression in the cochlea. Completion of these aims will provide the following expected outcomes. First, we will have a clear picture of the expression profile of Diap3 in wild-type mice. Second, we will have characterized mouse models that will provide researchers with a new tool for testing therapies and for examining downstream effectors of Diap3 protein. Third, we will gain understanding of how Diap3 overexpression may lead to cytoskeletal changes that impact the auditory system.
We have identified a gene, DIAPH3, that when overexpressed causes deafness. By elucidating its role in mice, we expect to help clarify an as yet unknown mechanism involved in the process of normal hearing. This new mouse model will be an important tool for testing potential therapies and will allow us to attain our ultimate goal of greater understanding of this form of deafness.
|Schoen, Cynthia J; Burmeister, Margit; Lesperance, Marci M (2013) Diaphanous homolog 3 (Diap3) overexpression causes progressive hearing loss and inner hair cell defects in a transgenic mouse model of human deafness. PLoS One 8:e56520|