Abstract
Otitis media (OM), inflammation of the middle ear (ME), is a common cause of conductive hearing impairment. Despite the importance of the disease, the aetiology of chronic and recurrent forms of middle ear inflammatory disease remains poorly understood. Studies of the human population suggest that there is a significant genetic component predisposing to the development of chronic OM, although the underlying genes are largely unknown. Using N-ethyl-N-nitrosourea mutagenesis we identified a recessive mouse mutant, edison, that spontaneously develops a conductive hearing loss due to chronic OM. The causal mutation was identified as a missense change, L972P, in the Nischarin (NISCH) gene. edison mice develop a serous or granulocytic effusion, increasingly macrophage and neutrophil rich with age, along with a thickened, inflamed mucoperiosteum. We also identified a second hypomorphic allele, V33A, with only modest increases in auditory thresholds and reduced incidence of OM. NISCH interacts with several proteins, including ITGA5 that is thought to have a role in modulating VEGF-induced angiogenesis and vascularization. We identified a significant genetic interaction between Nisch and Itga5; mice heterozygous for Itga5-null and homozygous for edison mutations display a significantly increased penetrance and severity of chronic OM. In order to understand the pathological mechanisms underlying the OM phenotype, we studied interacting partners to NISCH along with downstream signalling molecules in the middle ear epithelia of edison mouse. Our analysis implicates PAK1 and RAC1, and downstream signalling in LIMK1 and NF-κB pathways in the development of chronic OM.
Highlights
Otitis media (OM) is characterised by inflammation of the middle ear (ME), often associated with a conductive hearing impairment, and is the commonest cause of hearing loss in children
There is evidence that a significant genetic component contributes towards the development of recurrent and chronic forms of OM
Our molecular analysis of the mutation reveals the underlying pathological mechanisms and pathways involved in OM in the edison mouse, involving PAK1, RAC1 and downstream signalling in LIMK1 and NF-κB pathways
Summary
Otitis media (OM) is characterised by inflammation of the middle ear (ME), often associated with a conductive hearing impairment, and is the commonest cause of hearing loss in children. Evidence from studies of the human population suggests that there is a significant genetic component predisposing to the development of recurrent and chronic forms of OM [2,3]. Despite the importance of the disease, many of the genes involved in OM susceptibility have still yet to be identified. The use of mouse models is the most promising method to identify candidate loci underlying susceptibility to OM. Mouse models have highlighted the role of Toll-like receptors (TLRs) in acute OM, in particular the protection against commensal and pathogenic bacteria, and that persistent NF-κB or TGF-β signalling could be two mechanisms leading to the overactive proinflammatory response seen in chronic OM [4,5]
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