Whole-exome sequencing identifies two novel mutations in KCNQ4 in individuals with nonsyndromic hearing loss

Jinsei Jung, Hyun Been Choi, Young Ik Koh, John Hoon Rim, Hye Ji Choi, Sung Huhn Kim, Jae Hyun Lee, Jieun An, Ami Kim, Joon Suk Lee, Sun Young Joo, Seyoung Yu, Jae Young Choi, Tong Mook Kang, Heon Yung Gee

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Abstract

Mutations in potassium voltage-gated channel subfamily Q member 4 (KCNQ4) are etiologically linked to a type of nonsyndromic hearing loss, deafness nonsyndromic autosomal dominant 2 (DFNA2). We performed whole-exome sequencing for 98 families with hearing loss and found mutations in KCNQ4 in five families. In this study, we characterized two novel mutations in KCNQ4: a missense mutation (c.796G>T; p.Asp266Tyr) and an in-frame deletion mutation (c.259_267del; p.Val87_Asn89del). p.Asp266Tyr located in the channel pore region resulted in early onset and moderate hearing loss, whereas p.Val87_Asn89del located in the N-terminal cytoplasmic region resulted in late onset and high frequency-specific hearing loss. When heterologously expressed in HEK 293 T cells, both mutant proteins did not show defects in protein trafficking to the plasma membrane or in interactions with wild-type (WT) KCNQ4 channels. Patch-clamp analysis demonstrated that both p.Asp266Tyr and p.Val87_Asn89del mutant channels lost conductance and were completely unresponsive to KCNQ activators, such as retigabine, zinc pyrithione, and ML213. Channels assembled from WT-p.Asp266Tyr concatemers, like those from WT-WT concatemers, exhibited conductance and responsiveness to KCNQ activators. However, channels assembled from WT-p.Val87_Asn89del concatemers showed impaired conductance, suggesting that p.Val87_Asn89del caused complete loss-of-function with a strong dominant-negative effect on functional WT channels. Therefore, the main pathological mechanism may be related to loss of K + channel activity, not defects in trafficking.

Original languageEnglish
Article number16659
JournalScientific reports
Volume8
Issue number1
DOIs
Publication statusPublished - 2018 Dec 1

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Exome
Hearing Loss
Mutation
High-Frequency Hearing Loss
Voltage-Gated Potassium Channels
Sequence Deletion
HEK293 Cells
Protein Transport
Missense Mutation
Mutant Proteins
Cell Membrane
T-Lymphocytes
Nonsyndromic Deafness

All Science Journal Classification (ASJC) codes

  • General

Cite this

Jung, Jinsei ; Choi, Hyun Been ; Koh, Young Ik ; Rim, John Hoon ; Choi, Hye Ji ; Kim, Sung Huhn ; Lee, Jae Hyun ; An, Jieun ; Kim, Ami ; Lee, Joon Suk ; Joo, Sun Young ; Yu, Seyoung ; Choi, Jae Young ; Kang, Tong Mook ; Gee, Heon Yung. / Whole-exome sequencing identifies two novel mutations in KCNQ4 in individuals with nonsyndromic hearing loss. In: Scientific reports. 2018 ; Vol. 8, No. 1.
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title = "Whole-exome sequencing identifies two novel mutations in KCNQ4 in individuals with nonsyndromic hearing loss",
abstract = "Mutations in potassium voltage-gated channel subfamily Q member 4 (KCNQ4) are etiologically linked to a type of nonsyndromic hearing loss, deafness nonsyndromic autosomal dominant 2 (DFNA2). We performed whole-exome sequencing for 98 families with hearing loss and found mutations in KCNQ4 in five families. In this study, we characterized two novel mutations in KCNQ4: a missense mutation (c.796G>T; p.Asp266Tyr) and an in-frame deletion mutation (c.259_267del; p.Val87_Asn89del). p.Asp266Tyr located in the channel pore region resulted in early onset and moderate hearing loss, whereas p.Val87_Asn89del located in the N-terminal cytoplasmic region resulted in late onset and high frequency-specific hearing loss. When heterologously expressed in HEK 293 T cells, both mutant proteins did not show defects in protein trafficking to the plasma membrane or in interactions with wild-type (WT) KCNQ4 channels. Patch-clamp analysis demonstrated that both p.Asp266Tyr and p.Val87_Asn89del mutant channels lost conductance and were completely unresponsive to KCNQ activators, such as retigabine, zinc pyrithione, and ML213. Channels assembled from WT-p.Asp266Tyr concatemers, like those from WT-WT concatemers, exhibited conductance and responsiveness to KCNQ activators. However, channels assembled from WT-p.Val87_Asn89del concatemers showed impaired conductance, suggesting that p.Val87_Asn89del caused complete loss-of-function with a strong dominant-negative effect on functional WT channels. Therefore, the main pathological mechanism may be related to loss of K + channel activity, not defects in trafficking.",
author = "Jinsei Jung and Choi, {Hyun Been} and Koh, {Young Ik} and Rim, {John Hoon} and Choi, {Hye Ji} and Kim, {Sung Huhn} and Lee, {Jae Hyun} and Jieun An and Ami Kim and Lee, {Joon Suk} and Joo, {Sun Young} and Seyoung Yu and Choi, {Jae Young} and Kang, {Tong Mook} and Gee, {Heon Yung}",
year = "2018",
month = "12",
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doi = "10.1038/s41598-018-34876-9",
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Jung, J, Choi, HB, Koh, YI, Rim, JH, Choi, HJ, Kim, SH, Lee, JH, An, J, Kim, A, Lee, JS, Joo, SY, Yu, S, Choi, JY, Kang, TM & Gee, HY 2018, 'Whole-exome sequencing identifies two novel mutations in KCNQ4 in individuals with nonsyndromic hearing loss', Scientific reports, vol. 8, no. 1, 16659. https://doi.org/10.1038/s41598-018-34876-9

Whole-exome sequencing identifies two novel mutations in KCNQ4 in individuals with nonsyndromic hearing loss. / Jung, Jinsei; Choi, Hyun Been; Koh, Young Ik; Rim, John Hoon; Choi, Hye Ji; Kim, Sung Huhn; Lee, Jae Hyun; An, Jieun; Kim, Ami; Lee, Joon Suk; Joo, Sun Young; Yu, Seyoung; Choi, Jae Young; Kang, Tong Mook; Gee, Heon Yung.

In: Scientific reports, Vol. 8, No. 1, 16659, 01.12.2018.

Research output: Contribution to journalArticle

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T1 - Whole-exome sequencing identifies two novel mutations in KCNQ4 in individuals with nonsyndromic hearing loss

AU - Jung, Jinsei

AU - Choi, Hyun Been

AU - Koh, Young Ik

AU - Rim, John Hoon

AU - Choi, Hye Ji

AU - Kim, Sung Huhn

AU - Lee, Jae Hyun

AU - An, Jieun

AU - Kim, Ami

AU - Lee, Joon Suk

AU - Joo, Sun Young

AU - Yu, Seyoung

AU - Choi, Jae Young

AU - Kang, Tong Mook

AU - Gee, Heon Yung

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Mutations in potassium voltage-gated channel subfamily Q member 4 (KCNQ4) are etiologically linked to a type of nonsyndromic hearing loss, deafness nonsyndromic autosomal dominant 2 (DFNA2). We performed whole-exome sequencing for 98 families with hearing loss and found mutations in KCNQ4 in five families. In this study, we characterized two novel mutations in KCNQ4: a missense mutation (c.796G>T; p.Asp266Tyr) and an in-frame deletion mutation (c.259_267del; p.Val87_Asn89del). p.Asp266Tyr located in the channel pore region resulted in early onset and moderate hearing loss, whereas p.Val87_Asn89del located in the N-terminal cytoplasmic region resulted in late onset and high frequency-specific hearing loss. When heterologously expressed in HEK 293 T cells, both mutant proteins did not show defects in protein trafficking to the plasma membrane or in interactions with wild-type (WT) KCNQ4 channels. Patch-clamp analysis demonstrated that both p.Asp266Tyr and p.Val87_Asn89del mutant channels lost conductance and were completely unresponsive to KCNQ activators, such as retigabine, zinc pyrithione, and ML213. Channels assembled from WT-p.Asp266Tyr concatemers, like those from WT-WT concatemers, exhibited conductance and responsiveness to KCNQ activators. However, channels assembled from WT-p.Val87_Asn89del concatemers showed impaired conductance, suggesting that p.Val87_Asn89del caused complete loss-of-function with a strong dominant-negative effect on functional WT channels. Therefore, the main pathological mechanism may be related to loss of K + channel activity, not defects in trafficking.

AB - Mutations in potassium voltage-gated channel subfamily Q member 4 (KCNQ4) are etiologically linked to a type of nonsyndromic hearing loss, deafness nonsyndromic autosomal dominant 2 (DFNA2). We performed whole-exome sequencing for 98 families with hearing loss and found mutations in KCNQ4 in five families. In this study, we characterized two novel mutations in KCNQ4: a missense mutation (c.796G>T; p.Asp266Tyr) and an in-frame deletion mutation (c.259_267del; p.Val87_Asn89del). p.Asp266Tyr located in the channel pore region resulted in early onset and moderate hearing loss, whereas p.Val87_Asn89del located in the N-terminal cytoplasmic region resulted in late onset and high frequency-specific hearing loss. When heterologously expressed in HEK 293 T cells, both mutant proteins did not show defects in protein trafficking to the plasma membrane or in interactions with wild-type (WT) KCNQ4 channels. Patch-clamp analysis demonstrated that both p.Asp266Tyr and p.Val87_Asn89del mutant channels lost conductance and were completely unresponsive to KCNQ activators, such as retigabine, zinc pyrithione, and ML213. Channels assembled from WT-p.Asp266Tyr concatemers, like those from WT-WT concatemers, exhibited conductance and responsiveness to KCNQ activators. However, channels assembled from WT-p.Val87_Asn89del concatemers showed impaired conductance, suggesting that p.Val87_Asn89del caused complete loss-of-function with a strong dominant-negative effect on functional WT channels. Therefore, the main pathological mechanism may be related to loss of K + channel activity, not defects in trafficking.

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