Cell death-inducing cytotoxicity in truncated KCNQ4 variants associated with DFNA2 hearing loss.
Cell death-inducing cytotoxicity in truncated KCNQ4 variants associated with DFNA2 hearing loss.
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DOI：
10.1242/dmm.049015
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发表时间：
2021-11-01
影响因子：
4.3
通讯作者：
Homma K
中科院分区：
文献类型：
--
作者：
Kojima T;Wasano K;Takahashi S;Homma K
KCNQ 4编码同源四聚体电压依赖性钾离子通道Kv7.4，是常染色体显性非综合征型感音神经性听力损失（DFNA 2）的致病基因。显性负抑制解释了许多DFNA 2相关KCNQ 4变体的显性遗传。此外，单倍不足已被假定为缺乏C-末端四聚化区域的截短Kv7.4变体的病理机制，因为它们不太可能发挥显性负抑制作用。这种截短的Kv7.4变体在杂合子时应导致相对轻度的听力损失;然而，情况并非总是如此。在这项研究中，我们在异源表达系统中表征了Kv7.4Q71fs（c.211delC）、Kv7.4W242X（c.725G>A）和Kv7.4A349fs（c.1044_1051del8），并发现这些截短的Kv7.4变体的表达诱导细胞死亡。我们还在截短的Kv7.1（KCNQ 1）变体中发现了类似的细胞死亡诱导细胞毒性作用，这表明我们的研究结果的一般性可以解释许多（如果不是大多数）截短的Kv 7变体的显性遗传。此外，我们发现自噬诱导剂的应用可以改善细胞毒性，为开发Kv7.4变体的替代治疗策略提供了新的见解。总结：缺乏C-末端四聚化结构域的截短KCNQ 4变体的表达导致细胞死亡诱导细胞毒性，为DFNA 2听力损失的替代治疗策略的发展提供了新的见解。
KCNQ4 encodes the homotetrameric voltage-dependent potassium ion channel Kv7.4, and is the causative gene for autosomal dominant nonsyndromic sensorineural hearing loss, DFNA2. Dominant-negative inhibition accounts for the observed dominant inheritance of many DFNA2-associated KCNQ4 variants. In addition, haploinsufficiency has been presumed as the pathological mechanism for truncated Kv7.4 variants lacking the C-terminal tetramerization region, as they are unlikely to exert a dominant-negative inhibitory effect. Such truncated Kv7.4 variants should result in relatively mild hearing loss when heterozygous; however, this is not always the case. In this study, we characterized Kv7.4Q71fs (c.211delC), Kv7.4W242X (c.725G>A) and Kv7.4A349fs (c.1044_1051del8) in heterologous expression systems and found that expression of these truncated Kv7.4 variants induced cell death. We also found similar cell death-inducing cytotoxic effects in truncated Kv7.1 (KCNQ1) variants, suggesting that the generality of our findings could account for the dominant inheritance of many, if not most, truncated Kv7 variants. Moreover, we found that the application of autophagy inducers can ameliorate the cytotoxicity, providing a novel insight for the development of alternative therapeutic strategies for Kv7.4 variants. Summary: Expression of truncated KCNQ4 variants lacking the C-terminal tetramerization domain results in cell-death inducing cytotoxicity, providing novel insight into the development of alternative therapeutic strategies for DFNA2 hearing loss.
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影响因子：
6.1
作者：
Kim EC;Zhang J;Pang W;Wang S;Lee KY;Cavaretta JP;Walters J;Procko E;Tsai NP;Chung HJ
通讯作者：
Chung HJ
影响因子：
12.8
作者：
Jung, Jinsei;Lin, Haiyue;Gee, Heon Yung
通讯作者：
Gee, Heon Yung
影响因子：
5.3
作者：
Gao Y;Yechikov S;Vázquez AE;Chen D;Nie L
通讯作者：
Nie L
影响因子：
16.2
作者：
Howard, Rebecca J.;Clark, Kimberly A.;Minor, Daniel L., Jr.
通讯作者：
Minor, Daniel L., Jr.
DOI：
10.1073/pnas.90.18.8347
发表时间：
1993-09-15
影响因子：
11.1
作者：
EVANS, BN;DALLOS, P
通讯作者：
DALLOS, P