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 , Fanny Kortüm , Anna Möllring , Lev Grinstein , Jonas Denecke , Malik Alawi , Robert Bähring , 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><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.
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.