Hardisty-Hughes Rachel E, Tateossian Hilda, Morse Susan A, Romero M Rosario, Middleton Alice, Tymowska-Lalanne Zuzanna, Hunter A Jackie, Cheeseman Michael, Brown Steve D M
MRC Mammalian Genetics Unit, Harwell, UK.
Hum Mol Genet. 2006 Nov 15;15(22):3273-9. doi: 10.1093/hmg/ddl403. Epub 2006 Oct 11.
Otitis media (OM), inflammation of the middle ear, is the most common cause of hearing impairment and surgery in children. Recurrent and chronic forms of OM 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 OM (Hardisty, R.E., Erven, A., Logan, K., Morse, S., Guionaud, S., Sancho-Oliver, S., Hunter, A.J., Brown, S.D. and Steel, K.P. (2003) The deaf mouse mutant Jeff (Jf) is a single gene model of otitis media. J. Assoc. Res. Otolaryngol., 4, 130-138.) and represent a model for chronic forms of OM 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 OM 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 aetiology of OM. 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.
中耳炎（OM），即中耳的炎症，是儿童听力障碍和手术的最常见原因。已知复发性和慢性形式的中耳炎具有很强的遗传成分，但对于人类群体中涉及的潜在基因却一无所知。我们之前鉴定出一种新型的半显性小鼠突变体Jeff，其中杂合子会发展为慢性化脓性中耳炎（哈迪斯蒂，R.E.，埃尔文，A.，洛根，K.，莫尔斯，S.，吉奥诺，S.，桑乔 - 奥利弗，S.，亨特，A.J.，布朗，S.D.和斯蒂尔，K.P.（2003年）耳聋小鼠突变体Jeff（Jf）是中耳炎的单基因模型。《耳鼻咽喉头颈外科研究协会杂志》，4, 130 - 138.），它代表了人类慢性中耳炎的一种模型。我们在此证明Jeff在一个F - box基因Fbxo11中携带一个突变。Fbxo11从胚胎后期到出生后第13天在中耳上皮细胞中表达。与Jeff杂合子不同，Jeff纯合子表现出腭裂、面部裂隙和围产期致死性。我们还分离并鉴定了另一个低表达突变等位基因Mutt。Mutt杂合子不会发展为中耳炎，但Mutt纯合子也表现出面部裂隙和腭裂异常。FBXO11是首批被鉴定出的、对中耳炎遗传病因有贡献作用的分子之一。此外，Fbxo11突变等位基因的隐性效应表明该基因是人类群体腭裂研究的一个重要候选基因。
