Loss-of-function variant in KCNH3 is associated with global developmental delay, autistic behavior, insomnia, and nocturnal seizures

IF 2.7 3区 医学 Q2 CLINICAL NEUROLOGY
Christiane K. Bauer , Fanny Kortüm , Anna Möllring , Lev Grinstein , Jonas Denecke , Malik Alawi , Robert Bähring , Frederike L. Harms
{"title":"Loss-of-function variant in KCNH3 is associated with global developmental delay, autistic behavior, insomnia, and nocturnal seizures","authors":"Christiane K. Bauer ,&nbsp;Fanny Kortüm ,&nbsp;Anna Möllring ,&nbsp;Lev Grinstein ,&nbsp;Jonas Denecke ,&nbsp;Malik Alawi ,&nbsp;Robert Bähring ,&nbsp;Frederike L. Harms","doi":"10.1016/j.seizure.2025.03.014","DOIUrl":null,"url":null,"abstract":"<div><h3>Introduction</h3><div>The <em>KCNH</em> gene family encodes voltage-gated potassium (Kv) channels of the EAG subtype covering three subfamilies (Kv10–12). EAG channels are involved in the control of cardiac and neuronal excitation, and pathogenic variants in <em>KCNH</em> genes encoding Kv10 (eag) and Kv11 (erg) subfamily members cause a broad clinical spectrum ranging from cardiac arrhythmia to neurodevelopmental syndromes. However, no pathogenic variants have been hitherto reported for <em>KCNH</em> genes encoding Kv12 (elk) subfamily members.</div></div><div><h3>Methods</h3><div>Clinical, genomic, and functional studies were performed, including voltage-clamp experiments using heterologous channel expression in <em>Xenopus</em> oocytes.</div></div><div><h3>Results</h3><div>We examined an eight-year-old girl presenting with global developmental delay, intellectual disability, autistic and aggressive behavior, hyperactivity, insomnia, and nocturnal seizures. Focal seizures were successfully treated with sulthiame, which reduced the occurrence of temporo-parietal spike-wave paroxysms. Trio exome sequencing revealed a heterozygous <em>de novo</em> missense variant, NM_012284.3:c.1112C&gt;<em>T</em>; p.(Ala371Val), in <em>KCNH3</em>, which encodes the Kv channel α-subunit Kv12.2. The amino acid substitution associated with the <em>KCNH3</em> variant identified in the patient is located at a site highly conserved in EAG channels. The analogous variant in <em>KCNH2</em> causes long-QT-syndrome 2, and has also been associated with epilepsy. Electrophysiological characterization of the <em>KCNH3</em> p.(Ala371Val) variant demonstrated loss-of-function of the mutant Kv12.2 channels and strongly reduced current amplitudes upon co-expression of wildtype and mutant channel subunits in a dominant-negative manner.</div></div><div><h3>Conclusion</h3><div>Our results propose <em>KCNH3</em>, which is primarily expressed in the nervous system, as a new disease gene associated with a neurodevelopmental phenotype including seizures.</div></div>","PeriodicalId":49552,"journal":{"name":"Seizure-European Journal of Epilepsy","volume":"129 ","pages":"Pages 14-21"},"PeriodicalIF":2.7000,"publicationDate":"2025-03-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Seizure-European Journal of Epilepsy","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1059131125000780","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Introduction

The KCNH gene family encodes voltage-gated potassium (Kv) channels of the EAG subtype covering three subfamilies (Kv10–12). EAG channels are involved in the control of cardiac and neuronal excitation, and pathogenic variants in KCNH genes encoding Kv10 (eag) and Kv11 (erg) subfamily members cause a broad clinical spectrum ranging from cardiac arrhythmia to neurodevelopmental syndromes. However, no pathogenic variants have been hitherto reported for KCNH genes encoding Kv12 (elk) subfamily members.

Methods

Clinical, genomic, and functional studies were performed, including voltage-clamp experiments using heterologous channel expression in Xenopus oocytes.

Results

We examined an eight-year-old girl presenting with global developmental delay, intellectual disability, autistic and aggressive behavior, hyperactivity, insomnia, and nocturnal seizures. Focal seizures were successfully treated with sulthiame, which reduced the occurrence of temporo-parietal spike-wave paroxysms. Trio exome sequencing revealed a heterozygous de novo missense variant, NM_012284.3:c.1112C>T; p.(Ala371Val), in KCNH3, which encodes the Kv channel α-subunit Kv12.2. The amino acid substitution associated with the KCNH3 variant identified in the patient is located at a site highly conserved in EAG channels. The analogous variant in KCNH2 causes long-QT-syndrome 2, and has also been associated with epilepsy. Electrophysiological characterization of the KCNH3 p.(Ala371Val) variant demonstrated loss-of-function of the mutant Kv12.2 channels and strongly reduced current amplitudes upon co-expression of wildtype and mutant channel subunits in a dominant-negative manner.

Conclusion

Our results propose KCNH3, which is primarily expressed in the nervous system, as a new disease gene associated with a neurodevelopmental phenotype including seizures.
求助全文
约1分钟内获得全文 求助全文
来源期刊
Seizure-European Journal of Epilepsy
Seizure-European Journal of Epilepsy 医学-临床神经学
CiteScore
5.60
自引率
6.70%
发文量
231
审稿时长
34 days
期刊介绍: Seizure - European Journal of Epilepsy is an international journal owned by Epilepsy Action (the largest member led epilepsy organisation in the UK). It provides a forum for papers on all topics related to epilepsy and seizure disorders.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信