Cell death-inducing cytotoxicity in truncated KCNQ4 variants associated with DFNA2 hearing loss

Takashi Kojima; Koichiro Wasano; Satoe Takahashi; Kazuaki Homma

doi:10.1242/dmm.049015

Cell death-inducing cytotoxicity in truncated KCNQ4 variants associated with DFNA2 hearing loss

Takashi Kojima, Koichiro Wasano^*, Satoe Takahashi, Kazuaki Homma^*

^*Corresponding author for this work

Otolaryngology

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

Abstract

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 Kv7.4^Q71fs (c.211delC), Kv7.4^W242X (c.725G>A) and Kv7.4^A349fs (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.

Original language	English (US)
Article number	dmm049015
Journal	DMM Disease Models and Mechanisms
Volume	14
Issue number	11
DOIs	https://doi.org/10.1242/dmm.049015
State	Published - Nov 2021

Funding

We thank Dr Michael Leitner for sharing plasmids encoding N-terminally GFP-tagged human Kv7.4 and N-terminally RFP-tagged human Kv7.4 constructs. We also thank Dr Federico Kalinec and Dr Tomohiro Shima for providing HEI-OC1 and LLC-PK1 cells, respectively. This work is supported by the National Institutes of Health (DC014553 and DC017482 to K.H.); a Japan Society for the Promotion of Science Grant-in-Aid for Scientific Research (18K16869 and 21K09574 to K.W.; 20K18330 to T.K.); a research promotion award from the Oto-Rhino-Laryngological Society of Japan (to K.W.); and the Hugh Knowles Center. This work is supported by the National Institutes of Health (DC014553 and DC017482 to K.H.); a Japan Society for the Promotion of Science Grant-in-Aid for Scientific Research (18K16869 and 21K09574 to K.W.; 20K18330 to T.K.); a research promotion award from the Oto-Rhino-Laryngological Society of Japan (to K.W.); and the Hugh Knowles Center.

Keywords

DFNA2
Hereditary hearing loss
KCNQ family
KCNQ4
Kv7.4
Potassium channel

ASJC Scopus subject areas

Neuroscience (miscellaneous)
Medicine (miscellaneous)
Immunology and Microbiology (miscellaneous)
General Biochemistry, Genetics and Molecular Biology

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10.1242/dmm.049015

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title = "Cell death-inducing cytotoxicity in truncated KCNQ4 variants associated with DFNA2 hearing loss",

abstract = "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.",

keywords = "DFNA2, Hereditary hearing loss, KCNQ family, KCNQ4, Kv7.4, Potassium channel",

author = "Takashi Kojima and Koichiro Wasano and Satoe Takahashi and Kazuaki Homma",

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AU - Kojima, Takashi

AU - Wasano, Koichiro

AU - Takahashi, Satoe

AU - Homma, Kazuaki

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N2 - 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.

AB - 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.

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KW - Potassium channel

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Cell death-inducing cytotoxicity in truncated KCNQ4 variants associated with DFNA2 hearing loss

Abstract

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Keywords

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