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Human Molecular Genetics Advance Access published online on October 11, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl403
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received July 10, 2006
Revised September 21, 2006
Accepted September 21, 2006

Article

A mutation in the f-box gene, fbxo11, causes otitis media in the jeff mouse

Rachel E. Hardisty-Hughes 1, Hilda Tateossian 1, Susan A. Morse 1, M. Rosario Romero 1, Alice Middleton 1, Zuzanna Tymowska-Lalanne 1, A. Jackie Hunter 2, Michael Cheeseman 3, and Steve D.M. Brown 1 *

1 MRC Mammalian Genetics Unit, Harwell, OX11 0RD, UK
2 GlaxoSmithKline Pharmaceuticals, New Frontiers Science Park, Harlow CM19 5AW, UK
3 MRC Mammalian Genetics Unit, Harwell, OX11 0RD, UK; MRC Mary Lyon Centre, Harwell, OX11 0RD, UK

* To whom correspondence should be addressed.
Steve D.M. Brown, E-mail: s.brown{at}har.mrc.ac.uk


  Abstract

Otitis media, inflammation of the middle ear, is the most common cause of hearing impairment and surgery in children. Recurrent (ROM) and chronic (COME) forms of otitis media are known to have a strong genetic component, but nothing is known of the underlying genes involved in the human population. We have previously identified a novel semi-dominant mouse mutant, Jeff, in which the heterozygotes develop chronic suppurative otitis media (1) and represent a model for chronic forms of otitis media in humans. We demonstrate here that Jeff carries a mutation in an F-box gene, Fbxo11. Fbxo11 is expressed in epithelial cells of the middle ears from late embryonic stages through to day 13 of postnatal life. In contrast to Jeff heterozygotes, Jeff homozygotes show cleft palate, facial clefting and perinatal lethality. We have also isolated and characterized an additional hypomorphic mutant allele, Mutt. Mutt heterozygotes do not develop otitis media but Mutt homozygotes also show facial clefting and cleft palate abnormalities. FBXO11 is one of the first molecules to be identified, contributing to the genetic etiology of otitis media. In addition, the recessive effects of mutant alleles of Fbxo11 identify the gene as an important candidate for cleft palate studies in the human population.


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