The Genetic Identification and Physiological Characterization of a Novel Locus for Non-Progressive Hearing Loss on Mouse Chromosome 17

Abstract

Presbycusis, the progressive loss of hearing that occurs with aging, is a widespread condition with serious economical and social ramifications. Mice with age-related hearing loss (AHL) are commonly used as models of presbycusis because of their physiological and genetic homology to the human auditory system. The inbred mouse, 129S6/SvEvTac (129S6), often used to study its resistance to noise-induced hearing loss (NIHL) also has early-onset progressive hearing loss. However, little is known about the AHL trait of 129S6 or the identity of the underlying genes. This dissertation will describe studies conducted in 129S6 to understand the physiological mechanisms associated with AHL, its genetic manifestation and inheritance, and the physical location of the causal genes. Hearing sensitivity was examined in subjects using non-invasive auditory-evoked potentials and otoacoustic emissions. My research will show that hearing loss in 129S6 is early-onset, slow progressive, and a combination between sensory and conductive hearing loss. The research will show that hearing loss in the 129S6 strain is autosomal recessive with possible contribution by multiple genes. Selective breeding and the creation of recombinant-inbred mice were used to define a novel 3.7 megabase (Mb) locus for non-progressive hearing loss (<italic>nphl</italic>) on mouse proximal Chromosome (Chr) 17 that contributes exclusively to high-frequency (>24 kHz). The <italic>nphl</italic> locus is linked genetically to the same region on Chr 17 exhibiting resistance to NIHL and a progressive hearing loss (PHL) locus. Collectively, the work in this dissertation more accurately defines the physiological and genetic characteristics of hearing loss in the 129S6 mouse. The understanding of this phenotype and the effects in mice will provide insight to future therapeutic advantages and preventative measures for homologous human conditions.