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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.

Original publication

DOI

10.1371/journal.pgen.1006969

Type

Journal article

Journal

PLoS Genet

Publication Date

08/2017

Volume

13

Keywords

Alleles, Animals, Chromosome Mapping, Chronic Disease, Disease Models, Animal, Ear, Middle, Ethylnitrosourea, Female, Genotyping Techniques, Heterozygote, Homozygote, Humans, Inflammation, Integrin alpha6, Intracellular Signaling Peptides and Proteins, Lim Kinases, Male, Mice, Mice, Knockout, Mutation, Missense, NF-kappa B, Neuropeptides, Otitis Media, Penetrance, Sequence Analysis, DNA, Up-Regulation, Vascular Endothelial Growth Factor A, p21-Activated Kinases, rac1 GTP-Binding Protein