{"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.
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.