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 i...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Non-syndromic Hearing Loss Autosomal Dominant Non-syndromic Deafness (DFNA2) KCNQ Channels Retigabine Strong Dominant-negative Effect Medicine R Science Q
Acceso en línea:	https://doaj.org/article/558c537c36fb4883a39a87434fd1dd89
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spelling	oai:doaj.org-article:558c537c36fb4883a39a87434fd1dd892021-12-02T15:08:12ZWhole-exome sequencing identifies two novel mutations in KCNQ4 in individuals with nonsyndromic hearing loss10.1038/s41598-018-34876-92045-2322https://doaj.org/article/558c537c36fb4883a39a87434fd1dd892018-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-34876-9https://doaj.org/toc/2045-2322Abstract 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.Jinsei JungHyun Been ChoiYoung Ik KohJohn Hoon RimHye Ji ChoiSung Huhn KimJae Hyun LeeJieun AnAmi KimJoon Suk LeeSun Young JooSeyoung YuJae Young ChoiTong Mook KangHeon Yung GeeNature PortfolioarticleNon-syndromic Hearing LossAutosomal Dominant Non-syndromic Deafness (DFNA2)KCNQ ChannelsRetigabineStrong Dominant-negative EffectMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-11 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Non-syndromic Hearing Loss Autosomal Dominant Non-syndromic Deafness (DFNA2) KCNQ Channels Retigabine Strong Dominant-negative Effect Medicine R Science Q
spellingShingle	Non-syndromic Hearing Loss Autosomal Dominant Non-syndromic Deafness (DFNA2) KCNQ Channels Retigabine Strong Dominant-negative Effect Medicine R Science Q 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 Whole-exome sequencing identifies two novel mutations in KCNQ4 in individuals with nonsyndromic hearing loss
description	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.
format	article
author	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
author_facet	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
author_sort	Jinsei Jung
title	Whole-exome sequencing identifies two novel mutations in KCNQ4 in individuals with nonsyndromic hearing loss
title_short	Whole-exome sequencing identifies two novel mutations in KCNQ4 in individuals with nonsyndromic hearing loss
title_full	Whole-exome sequencing identifies two novel mutations in KCNQ4 in individuals with nonsyndromic hearing loss
title_fullStr	Whole-exome sequencing identifies two novel mutations in KCNQ4 in individuals with nonsyndromic hearing loss
title_full_unstemmed	Whole-exome sequencing identifies two novel mutations in KCNQ4 in individuals with nonsyndromic hearing loss
title_sort	whole-exome sequencing identifies two novel mutations in kcnq4 in individuals with nonsyndromic hearing loss
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/558c537c36fb4883a39a87434fd1dd89
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Whole-exome sequencing identifies two novel mutations in KCNQ4 in individuals with nonsyndromic hearing loss

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