Methioninesulfoxide reductase B3 deficiency causes hearing loss due to stereocilia degeneration and apoptotic cell death in cochlear hair cells
Methioninesulfoxide reductase B3 deficiency causes hearing loss due to stereocilia degeneration and apoptotic cell death in cochlear hair cells
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DOI：
10.1093/hmg/ddt549
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发表时间：
2014-03-15
影响因子：
3.5
通讯作者：
Kim, Hwa-Young
中科院分区：
文献类型：
--
作者：
Kwon, Tae-Jun;Cho, Hyun-Ju;Kim, Hwa-Young
甲硫氨酸亚砜还原酶B3（MsrB 3）是一种蛋白质修复酶，特异性地将甲硫氨酸-R-亚砜还原为甲硫氨酸。最近的一项遗传研究表明，MSRB 3基因与人类耳聋DFNB 74中的常染色体隐性听力损失相关。然而，MSRB 3在听觉系统中的确切作用和听力损失的发病机制尚未确定。这项工作是第一次产生MsrB 3敲除小鼠，以阐明DFNB 74患者中观察到的听力损失的可能病理机制。我们发现纯合MsrB 3（-/-）小鼠严重耳聋，前庭功能基本不受影响，而杂合MsrB 3（-/-）小鼠表现出与野生型小鼠相似的正常听力。MsrB 3蛋白在耳蜗和前庭组织的感觉上皮中表达，分别在E15.5和E13.5开始。有趣的是，MsrB 3密集地定位于听觉毛细胞顶面上的静纤毛基部。MsrB 3缺陷导致P8开始的静纤毛束的进行性变性，随后是毛细胞的损失，导致MsrB 3（-/-）小鼠的深度耳聋。毛细胞损失似乎是由凋亡细胞死亡介导的，这是使用TUNEL和caspase 3免疫细胞化学测定的。总之，我们的数据表明，MSRB 3在维持毛细胞的完整性方面起着至关重要的作用，这可能解释了由MSRB 3缺乏引起的人类DFNB 74耳聋的发病机制。
Methionine sulfoxide reductase B3 (MsrB3) is a protein repair enzyme that specifically reduces methionine-R-sulfoxide to methionine. A recent genetic study showed that the MSRB3 gene is associated with autosomal recessive hearing loss in human deafness DFNB74. However, the precise role of MSRB3 in the auditory system and the pathogenesis of hearing loss have not yet been determined. This work is the first to generate MsrB3knockout mice to elucidate the possible pathological mechanisms of hearing loss observed in DFNB74 patients. We found that homozygous MsrB3(-/-) mice were profoundly deaf and had largely unaffected vestibular function, whereas heterozygous MsrB3(-/-) mice exhibited normal hearing similar to that of wild-type mice. The MsrB3 protein is expressed in the sensory epithelia of the cochlear and vestibular tissues, beginning at E15.5 and E13.5, respectively. Interestingly, MsrB3 is densely localized at the base of stereocilia on the apical surface of auditory hair cells. MsrB3 deficiency led to progressive degeneration of stereociliary bundles starting at P8, followed by a loss of hair cells, resulting in profound deafness in MsrB3(-/-) mice. The hair cell loss appeared to be mediated by apoptotic cell death, which was measured using TUNEL and caspase 3 immunocytochemistry. Taken together, our data suggest that MsrB3 plays an essential role in maintaining the integrity of hair cells, possibly explaining the pathogenesis of DFNB74 deafness in humans caused by MSRB3 deficiency.