DUOXA2介导的甲状腺激素合成对出生后听觉功能的成熟不可或缺。

文献信息

中文摘要

背景： 已鉴定出500多个与听力损失相关的基因，但大多数致聋突变的致病机制仍有待阐明，这阻碍了可行临床治疗策略的开发。临床研究表明，DUOXA2突变患者表现为黏膜免疫失调和甲状腺功能减退。此外，小鼠模型中的遗传学筛查将Duoxa2缺陷与严重耳聋联系起来，但其致病机制仍不清楚。方法：在本研究中，我们通过建立Duoxa2条件性敲除（cKO）小鼠模型，证明Duoxa2对正常听觉功能至关重要，并阐明了其潜在机制。结果：我们发现，Duoxa2缺陷通过扰乱甲状腺激素合成，损害了外毛细胞（OHCs）和血管纹（SV）——核心听觉组件——的结构和功能。Duoxa2 cKO小鼠表现出OHCs中静纤毛束排列紊乱、关键KCNQ4分布模式改变、带状突触定位异常以及SV中间细胞层内毛细血管扩张。值得注意的是，Atoh1-Cre驱动不仅在毛细胞中表达Cre重组酶，还在甲状腺中高表达。这一发现阐明了Atoh1-Duoxa2-/-小鼠中甲状腺激素水平降低的原因，并揭示了一种影响耳蜗功能的间接机制。虽然出生后甲状腺激素补充完全逆转了这些病理变化，但在成年期效果甚微。结论：我们的发现为不同甲状腺疾病与听力损伤之间的内在联系提供了见解，并为DUOXA2变异患者的临床干预提供了证据。

英文摘要

More than 500 genes associated with hearing loss have been identified, yet the pathogenic mechanisms underlying most deafness-causing mutations remain to be clarified, hindering the development of viable clinical therapeutic strategies. Clinical studies indicated that patients with DUOXA2 mutations present mucosal immune dysregulation and hypothyroidism. In addition, genetics screening in mouse models linked Duoxa2 deficiency to severe deafness, yet its pathogenic mechanism remains elusive. In this study, we demonstrated that Duoxa2 is essential for normal auditory function and clarified its underlying mechanism by establishing the Duoxa2 conditional knockout (cKO) mouse model. We found that Duoxa2 deficiency impairs the structure and function of outer hair cells (OHCs) and stria vascularis (SV), core auditory components, via disrupted thyroid hormone synthesis. Duoxa2 cKO mice exhibited disorganized stereociliary bundles in OHCs, altered distribution patterns of the critical KCNQ4, aberrant ribbon synapse localization, and capillary dilation within the intermediate cell layer of SV. Notably, Atoh1-Cre drivers not only express Cre recombinase in hair cells but also show high expression in thyroid. This finding elucidates the reduced thyroid hormone levels in Atoh1-Duoxa2-/- mice and reveals an indirect mechanism affecting cochlear function. While postnatal thyroid hormone supplementation completely reversed these pathological changes, the effect was minimal in adulthood. Our findings provided insights into the intrinsic link between distinct thyroid disorders and hearing impairment and offered evidence for clinical intervention in patients with DUOXA2 variants.