The Mouse Mutant Model for Chronic Otitis Media Manifests Gain-of-Function as Well as Loss-of-Function Effects.

Chronic otitis media (OM) is the most common cause of hearing loss worldwide, yet the underlying genetics and molecular pathology are poorly understood. The mouse mutant is a single gene mouse model for OM identified from a deafness screen as part of an ENU mutagenesis program at MRC Harwell. carries a missense mutation in the gene. heterozygotes ( develop chronic OM at weaning and have reduced hearing. Homozygotes ( ) display perinatal lethality due to developmental epithelial abnormalities. In order to investigate the role of FBXO11 and the type of mutation responsible for the phenotype of the mice, a knock-out mouse model was created and compared to . Surprisingly, the heterozygote knock-outs ( ) show a much milder phenotype: they do not display any auditory deficit and only some of them have thickened middle ear epithelial lining with no fluid in the ear. In addition, the knock-out homozygote embryos ( ), as well as the compound heterozygotes ( ) show only mild abnormalities compared to homozygotes ( ). Interestingly, 3 days after intranasal inoculation of the mice with non-typeable (NTHi) a proportion of them have inflamed middle ear mucosa and fluid accumulation in the ear suggesting that the knock-out mice are predisposed to NTHi induced middle ear inflammation. In conclusion, the finding that the phenotype of the mutant is much more severe than the knock-out indicates that the mutation in manifests gain-of-function as well as loss-of-function effects at both embryonic and adult stages.