AUTHOR=Kubinyecz Oana , Vikhe Pratik P. , Purnell Thomas , Brown Steve D. M. , Tateossian Hilda 

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

JOURNAL=Frontiers in Genetics

VOLUME=11

YEAR=2020

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2020.00498

DOI=10.3389/fgene.2020.00498

ISSN=1664-8021

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