A humanized murine model, demonstrating dominant progressive hearing loss caused by a novel KCNQ4 mutation (p.G228D) from a large Chinese family
A humanized murine model, demonstrating dominant progressive hearing loss caused by a novel KCNQ4 mutation (p.G228D) from a large Chinese family
复制标题
人源化小鼠模型，显示由来自一个中国大家庭的新型 KCNQ4 突变 (p.G228D) 引起的显性进行性听力损失
DOI：
10.1111/cge.14164
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发表时间：
2022-05-28
影响因子：
3.5
通讯作者：
Li, Huawei
中科院分区：
文献类型：
--
作者：
Cui, Chong;Zhang, Luping;Li, Huawei
KCNQ4致病变异体导致DFNA2非综合征性耳聋。然而，对KCNQ4与听力之间的基因-表型相关性的了解是有限的。在这里，我们从一个中国家庭中发现了一个新的KCNQ4突变p.G228D，包括以高频听力损失为特征的杂合子和具有更严重听力损失的纯合子。我们构建了一种人源化同源Kcnq4突变的小鼠模型。杂合子在4周时出现中频和高频听力损失，12周时向所有频率的听力损失发展，而纯合子在8周时出现重度至重度听力损失。外毛细胞从耳蜗基底部至耳蜗顶回变性。细胞内K+电流减少，去极化静息电位降低。值得注意的是，我们在8-12周观察到频率高于32 kHz的区域内毛细胞(IHC)的丢失。结果表明，随着时间的推移，毛细胞和间质细胞的退化可能导致DFNA2的高频听力损失。我们的发现拓宽了KCNQ4的变异体，并提供了一种新的进行性听力损失小鼠模型，这有助于理解DFNA2进行性听力损失的发病机制和最终的治疗。
The pathogenic variants in KCNQ4 cause DFNA2 nonsyndromic hearing loss. However, the understanding of genotype-phenotype correlations between KCNQ4 and hearing is limited. Here, we identified a novel KCNQ4 mutation p.G228D from a Chinese family, including heterozygotes characterized by high-frequency hearing loss that is progressive across all frequencies and homozygotes with more severe hearing loss. We constructed a novel murine model with humanized homologous Kcnq4 mutation. The heterozygotes had mid-frequency and high-frequency hearing loss at 4 weeks, and moved toward all frequencies hearing loss at 12 weeks, while the homozygotes had severe-to-profound hearing loss at 8 weeks. The degeneration of outer hair cells (OHCs) was observed from basal to apical turn of cochlea. The reduced K+ currents and depolarized resting potentials were revealed in OHCs. Remarkably, we observed the loss of inner hair cells (IHCs) in the region corresponding to the frequency above 32 kHz at 8-12 weeks. The results suggest the degeneration of OHCs and IHCs may contribute to high-frequency hearing loss in DFNA2 over time. Our findings broaden the variants of KCNQ4 and provide a novel mouse model of progressive hearing loss, which contributes to an understanding of pathogenic mechanism and eventually treatment of DFNA2 progressive hearing loss.