MRC Mammalian Genetics Unit, Harwell, UK
Hum Mol Genet. 2013 Jul 1;22(13):2553-65. doi: 10.1093/hmg/ddt103. Epub 2013 Mar 3.
Otitis media with effusion (OME) is the most common cause of hearing loss in children and tympanostomy to alleviate the condition remains the commonest surgical intervention in children in the developed world. Chronic and recurrent forms of OM are known to have a very significant genetic component, however, until recently little was known of the underlying genes involved. The identification of mouse models of chronic OM has indicated a role of transforming growth factor beta (TGFβ) signalling and its impact on responses to hypoxia in the inflamed middle ear. We have, therefore, investigated the role of TGFβ signalling and identified and characterized a new model of chronic OM carrying a mutation in the gene for transforming growth interacting factor 1 (Tgif1). Tgif1 homozygous mutant mice have significantly raised auditory thresholds due to a conductive deafness arising from a chronic effusion starting at around 3 weeks of age. The OM is accompanied by a significant thickening of the middle ear mucosa lining, expansion of mucin-secreting goblet cell populations and raised levels of vascular endothelial growth factor, TNF-α and IL-1β in ear fluids. We also identified downstream effects on TGFβ signalling in middle ear epithelia at the time of development of chronic OM. Both phosphorylated SMAD2 and p21 levels were lowered in the homozygous mutant, demonstrating a suppression of the TGFβ pathway. The identification and characterization of the Tgif mutant supports the role of TGFβ signalling in the development of chronic OM and provides an important candidate gene for genetic studies in the human population.
中耳积液（OME）是儿童听力损失最常见的原因，在发达国家，鼓膜切开术是缓解这种疾病最常见的手术干预措施。已知慢性和复发性OME 具有非常显著的遗传成分，但直到最近，人们对涉及的潜在基因知之甚少。慢性OME 小鼠模型的鉴定表明转化生长因子β（TGFβ）信号及其对炎症中耳缺氧反应的影响起着重要作用。因此，我们研究了 TGFβ信号的作用，并鉴定和表征了一种携带转化生长相互作用因子 1（Tgif1）基因突变的慢性 OM 新模型。由于大约 3 周龄时开始出现慢性积液引起的传导性耳聋，Tgif1 纯合突变小鼠的听觉阈值显著升高。OME 伴随着中耳黏膜衬里的显著增厚、粘蛋白分泌杯状细胞群体的扩张以及耳液中血管内皮生长因子、TNF-α 和 IL-1β水平的升高。我们还在慢性 OM 发展时确定了中耳上皮中 TGFβ 信号的下游效应。在纯合突变体中，磷酸化 SMAD2 和 p21 的水平降低，表明 TGFβ 途径受到抑制。Tgif 突变体的鉴定和表征支持 TGFβ 信号在慢性 OM 发展中的作用，并为人类遗传研究提供了一个重要的候选基因。
