BK Channelopathies and KCNMA1-Linked Disease Models.

IF 15.7 1区 医学 Q1 PHYSIOLOGY Annual review of physiology Pub Date : 2024-02-12 Epub Date: 2023-10-31 DOI:10.1146/annurev-physiol-030323-042845
Andrea L Meredith
{"title":"BK Channelopathies and <i>KCNMA1</i>-Linked Disease Models.","authors":"Andrea L Meredith","doi":"10.1146/annurev-physiol-030323-042845","DOIUrl":null,"url":null,"abstract":"<p><p>Novel <i>KCNMA1</i> variants<i>,</i> encoding the BK K<sup>+</sup> channel, are associated with a debilitating dyskinesia and epilepsy syndrome. Neurodevelopmental delay, cognitive disability, and brain and structural malformations are also diagnosed at lower incidence. More than half of affected individuals present with a rare negative episodic motor disorder, paroxysmal nonkinesigenic dyskinesia (PNKD3). The mechanistic relationship of PNKD3 to epilepsy and the broader spectrum of <i>KCNMA1</i>-associated symptomology is unknown. This review summarizes patient-associated <i>KCNMA1</i> variants within the BK channel structure, functional classifications, genotype-phenotype associations, disease models, and treatment. Patient and transgenic animal data suggest delineation of gain-of-function (GOF) and loss-of-function <i>KCNMA1</i> neurogenetic disease, validating two heterozygous alleles encoding GOF BK channels (D434G and N999S) as causing seizure and PNKD3. This discovery led to a variant-defined therapeutic approach for PNKD3, providing initial insight into the neurological basis. A comprehensive clinical definition of monogenic <i>KCNMA1</i>-linked disease and the neuronal mechanisms currently remain priorities for continued investigation.</p>","PeriodicalId":8196,"journal":{"name":"Annual review of physiology","volume":null,"pages":null},"PeriodicalIF":15.7000,"publicationDate":"2024-02-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Annual review of physiology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1146/annurev-physiol-030323-042845","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2023/10/31 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"PHYSIOLOGY","Score":null,"Total":0}
引用次数: 0

Abstract

Novel KCNMA1 variants, encoding the BK K+ channel, are associated with a debilitating dyskinesia and epilepsy syndrome. Neurodevelopmental delay, cognitive disability, and brain and structural malformations are also diagnosed at lower incidence. More than half of affected individuals present with a rare negative episodic motor disorder, paroxysmal nonkinesigenic dyskinesia (PNKD3). The mechanistic relationship of PNKD3 to epilepsy and the broader spectrum of KCNMA1-associated symptomology is unknown. This review summarizes patient-associated KCNMA1 variants within the BK channel structure, functional classifications, genotype-phenotype associations, disease models, and treatment. Patient and transgenic animal data suggest delineation of gain-of-function (GOF) and loss-of-function KCNMA1 neurogenetic disease, validating two heterozygous alleles encoding GOF BK channels (D434G and N999S) as causing seizure and PNKD3. This discovery led to a variant-defined therapeutic approach for PNKD3, providing initial insight into the neurological basis. A comprehensive clinical definition of monogenic KCNMA1-linked disease and the neuronal mechanisms currently remain priorities for continued investigation.

查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
BK通道病和KCNMA1相关疾病模型。
编码BK K+通道的新型KCNMA1变体与衰弱性运动障碍和癫痫综合征有关。神经发育迟缓、认知功能障碍、大脑和结构畸形也被诊断为发病率较低。超过一半的受影响个体表现出罕见的负性发作性运动障碍,即发作性非运动性运动障碍(PNKD3)。PNKD3与癫痫的机制关系以及更广泛的KCNMA1相关症状尚不清楚。这篇综述总结了BK通道结构中与患者相关的KCNMA1变体、功能分类、基因型-表型关联、疾病模型和治疗。患者和转基因动物的数据表明,功能获得(GOF)和功能丧失KCNMA1神经源性疾病的描述,证实了编码GOF BK通道的两个杂合等位基因(D434G和N999S)导致癫痫发作和PNKD3。这一发现为PNKD3提供了一种变体定义的治疗方法,为神经基础提供了初步见解。单基因KCNMA1相关疾病的全面临床定义和神经元机制目前仍是继续研究的优先事项。《生理学年度评论》第86卷预计最终在线出版日期为2024年2月。请参阅http://www.annualreviews.org/page/journal/pubdates用于修订估算。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
来源期刊
Annual review of physiology
Annual review of physiology 医学-生理学
CiteScore
35.60
自引率
0.00%
发文量
41
期刊介绍: Since 1939, the Annual Review of Physiology has been highlighting significant developments in animal physiology. The journal covers diverse areas, including cardiovascular physiology, cell physiology, ecological, evolutionary, and comparative physiology, endocrinology, gastrointestinal physiology, neurophysiology, renal and electrolyte physiology, respiratory physiology, and special topics.
期刊最新文献
From Muscle-Based Nonshivering Thermogenesis to Malignant Hyperthermia in Mammals. The Calcium Homeostasis of Human Red Blood Cells in Health and Disease: Interactions of PIEZO1, the Plasma Membrane Calcium Pump, and Gardos Channels. Sex Differences in Electrophysiology and Calcium Handling in Atrial Health and Fibrillation. Transport and Immune Functions of the Lymphatic System. Spatial Transcriptomics of the Respiratory System.
×
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
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 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 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1