MOUSE MODELS OF THE HUMAN HEARING DISORDER DFNA15

St. Jude Children'S Research Hospital, Memphis TN

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Abstract

DESCRIPTION (from applicant's abstract): Although there have been dramatic successes in recent years in identifying multiple genes that can cause deafness in humans, very little is known about how mutations in these genes cause disease. We have recently succeeded in expressing a reporter gene specifically in hair cells in transgenic mice using a modified bacterial artificial chromosome (BAC). We found that in our transgenic mice the expression of the reporter gene recapitulates the pattern of the endogenous gene expression. Thus, this BAC transgenic technology can be widely used for making mouse models of dominant hearing disorders in which the disease genes display complex expression patterns, or in which the mutations are gain-of-function mutations. This application focuses on making mouse models of DFNA15, a progressive, nonsyndromic, autosomal dominant hearing loss in humans. Recently, an 8-bp deletion has been found in the POU4F3 gene in a family with DFNA15. In the inner ear, Pou4f3 is expressed specifically in hair cells from the earliest onset of development through adulthood. Targeted deletion of the Pou4f3 gene in mice suggested that the 8-bp deletion in POU4F3 does not represent a loss-of function allele, but rather a gain-of function allele of the POU4F3 gene. In this application we plan to test this hypothesis by: 1. generating transgenic mice that overexpress the mutant Pou4f3 gene in a pattern that recapitulates the pattern of endogenous Pou4f3 expression; 2. generating transgenic mice that overexpress the wild-type Pou4f3 gene in a pattern that recapitulates the pattern of endogenous Pou4f3 expression. The creation and characterization of mouse models of DFNA15 will facilitate the prevention and treatment of the disease in humans and will also lead to a better understanding of the normal function of the POU4F3 gene during hair cell development.