Modifiers of sensorineural hearing loss - Project Summary Congenital deafness is among the more prevalent chronic conditions seen in human infants, and genetic causes are thought to explain the majority of cases in developed countries. While progress has been made in identification of primary deafness causing genes, it is also evident that no given gene mutation acts alone. That is, additional variants throughout the genome (genetic modifiers) result in a spectrum of phenotypic outcomes. These modifiers are important to understand because they reveal new cellular and molecular mechanisms that participate in a phenotype of interest. They are also important for diagnostic, prognostic, therapeutic and patient management strategies. So far, there is no insight as to what these modifiers are or how they act. Waardenburg-Shah syndrome (WS4) is an example in which hearing loss is an incompletely penetrant trait within the larger group of patients with Hirschsprung disease (congenital gut motility disorder). Both are associated with mutations in endothelin signaling genes. As described in a recently published study, we recapitulated the variable penetrance of hearing impairment in endothelin signaling gene mutant mice by utilizing the genetically diverse outbred ICR strain background. We also determined that the primary cause of hearing impairment in these mice is in auditory synaptic function, and demonstrated unique and independent roles of endothelin signaling in spiral ganglia neurons and glia. This project seeks to identify genetic modifiers that influence the penetrance of hearing impairment in the context of endothelin receptor Ednrb deficiency. We performed a large scale genome wide association analysis which is uniquely possible with our mice, and identified two lead candidate genes that are presented here for further exploration. In Aim 1, we address the role of the gene Kcnj16 (encoding the potassium channel Kir5.1), which we propose influences hair cell excitability and auditory neuronal maturation. In Aim 2, we explore neuronal Dchs2 (which encodes a cadherin-type adhesion molecule) and address how it influences auditory synapse formation and function. The results from this study will elucidate genetic components of phenotypic heterogeneity and will reveal new mechanisms that are involved in auditory function. The experimental material is specific for WS4, although the insights are likely to be relevant to a much broader range of congenital hearing disorders in mice and humans.
