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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  Jeff  is a single gene mouse model for OM identified from a deafness screen as part of an ENU mutagenesis program at MRC Harwell.  Jeff  carries a missense mutation in the  Fbxo11  gene.  Jeff  heterozygotes ( Fbxo11  Jf/+  )  develop chronic OM at weaning and have reduced hearing. Homozygotes ( Fbxo11   Jf/Jf  ) 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  Jeff  mice, a knock-out mouse model was created and compared to  Jeff . Surprisingly, the heterozygote knock-outs ( Fbxo11   tm2b/+  ) 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 ( Fbxo11   tm2b/tm2b  ), as well as the compound heterozygotes ( Fbxo11   tm2b/Jf  ) show only mild abnormalities compared to  Jeff  homozygotes ( Fbxo11   Jf/Jf  ). Interestingly, 3 days after intranasal inoculation of the  Fbxo11   tm2b/+   mice with non-typeable  Haemophilus influenzae  (NTHi) a proportion of them have inflamed middle ear mucosa and fluid accumulation in the ear suggesting that the  Fbxo11  knock-out mice are predisposed to NTHi induced middle ear inflammation. In conclusion, the finding that the phenotype of the  Jeff  mutant is much more severe than the knock-out indicates that the mutation in  Jeff  manifests gain-of-function as well as loss-of-function effects at both embryonic and adult stages.

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