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
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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.

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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。
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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.
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