Tian Cong, Harris Belinda S, Johnson Kenneth R
The Jackson Laboratory, Bar Harbor, Maine, United States of America.
Graduate School of Biomedical Science and Engineering, University of Maine, Orono, Maine, United States of America.
PLoS One. 2016 Dec 13;11(12):e0168159. doi: 10.1371/journal.pone.0168159. eCollection 2016.
Otitis media (OM), inflammation of the middle ear, is a common cause of hearing loss in children and in patients with many different syndromic diseases. Studies of the human population and mouse models have revealed that OM is a multifactorial disease with many environmental and genetic contributing factors. Here, we report on otitis media-related hearing loss in asj (ages with stiffened joints) mutant mice, which bear a point mutation in the Enpp1 gene. Auditory-evoked brainstem response (ABR) measurements revealed that around 90% of the mutant mice (Enpp1asj/asj) tested had moderate to severe hearing impairment in at least one ear. The ABR thresholds were variable and generally elevated with age. We found otitis media with effusion (OME) in all of the hearing-impaired Enpp1asj/asj mice by anatomic and histological examinations. The volume and inflammatory cell content of the effusion varied among the asj mutant mice, but all mutants exhibited a thickened middle ear epithelium with fibrous polyps and more mucin-secreting goblet cells than controls. Other abnormalities observed in the Enpp1 mutant mice include over-ossification at the round window ridge, thickened and over-calcified stapedial artery, fusion of malleus and incus, and white patches on the inside of tympanic membrane, some of which are typical symptoms of tympanosclerosis. An excessive yellow discharge was detected in the outer ear canal of older asj mutant mice, with 100% penetrance by 5 months of age, and contributes to the progressive nature of the hearing loss. This is the first report of hearing loss and ear pathology associated with an Enpp1 mutation in mice. The Enpp1asj mutant mouse provides a new animal model for studying tympanosclerotic otitis and otitis media with effusion, and also provides a specific model for the hearing loss recently reported to be associated with human ENPP1 mutations causing generalized arterial calcification of infancy and hypophosphatemic rickets.
中耳炎（OM）是中耳的炎症，是儿童及患有多种不同综合征性疾病患者听力丧失的常见原因。对人类群体和小鼠模型的研究表明，中耳炎是一种多因素疾病，有许多环境和遗传因素。在此，我们报告了关节僵硬（asj）突变小鼠的中耳炎相关听力损失，这些小鼠的Enpp1基因存在一个点突变。听觉脑干反应（ABR）测量显示，约90%接受测试的突变小鼠（Enpp1asj/asj）至少一只耳朵有中度至重度听力障碍。ABR阈值各不相同，且通常随年龄升高。通过解剖和组织学检查，我们在所有听力受损的Enpp1asj/asj小鼠中发现了中耳积液（OME）。积液的量和炎症细胞含量在asj突变小鼠中各不相同，但所有突变小鼠的中耳上皮均增厚，伴有纤维性息肉，且分泌粘蛋白的杯状细胞比对照组更多。在Enpp1突变小鼠中观察到的其他异常包括圆窗嵴过度骨化、镫骨动脉增厚和过度钙化、锤骨和砧骨融合以及鼓膜内侧出现白色斑块，其中一些是鼓室硬化的典型症状。在老年asj突变小鼠的外耳道中检测到过多黄色分泌物，5月龄时发生率达100%，这导致了听力损失的进行性发展。这是小鼠中与Enpp1突变相关的听力损失和耳部病理学的首次报告。Enpp1asj突变小鼠为研究鼓室硬化性中耳炎和中耳积液提供了一种新的动物模型，也为最近报道的与导致婴儿期全身性动脉钙化和低磷性佝偻病的人类ENPP1突变相关的听力损失提供了一个特定模型。
