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    KCNMA1-linked channelopathy

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    Author
    Bailey, C.S.
    Moldenhauer, H.J.
    Park, S.M.
    Meredith, A.L.
    Date
    2019
    Journal
    The Journal of general physiology
    Publisher
    Rockefeller University Press
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1085/jgp.201912457
    Abstract
    KCNMA1 encodes the pore-forming α subunit of the "Big K+" (BK) large conductance calcium and voltage-activated K+ channel. BK channels are widely distributed across tissues, including both excitable and nonexcitable cells. Expression levels are highest in brain and muscle, where BK channels are critical regulators of neuronal excitability and muscle contractility. A global deletion in mouse (KCNMA1-/- ) is viable but exhibits pathophysiology in many organ systems. Yet despite the important roles in animal models, the consequences of dysfunctional BK channels in humans are not well characterized. Here, we summarize 16 rare KCNMA1 mutations identified in 37 patients dating back to 2005, with an array of clinically defined pathological phenotypes collectively referred to as "KCNMA1-linked channelopathy." These mutations encompass gain-of-function (GOF) and loss-of-function (LOF) alterations in BK channel activity, as well as several variants of unknown significance (VUS). Human KCNMA1 mutations are primarily associated with neurological conditions, including seizures, movement disorders, developmental delay, and intellectual disability. Due to the recent identification of additional patients, the spectrum of symptoms associated with KCNMA1 mutations has expanded but remains primarily defined by brain and muscle dysfunction. Emerging evidence suggests the functional BK channel alterations produced by different KCNMA1 alleles may associate with semi-distinct patient symptoms, such as paroxysmal nonkinesigenic dyskinesia (PNKD) with GOF and ataxia with LOF. However, due to the de novo origins for the majority of KCNMA1 mutations identified to date and the phenotypic variability exhibited by patients, additional evidence is required to establish causality in most cases. The symptomatic picture developing from patients with KCNMA1-linked channelopathy highlights the importance of better understanding the roles BK channels play in regulating cell excitability. Establishing causality between KCNMA1-linked BK channel dysfunction and specific patient symptoms may reveal new treatment approaches with the potential to increase therapeutic efficacy over current standard regimens. Copyright 2019 Bailey et al.
    Keyword
    KCNMA1
    Potassium Calcium-Activated Channel Subfamily M Alpha 1
    Channelopathies--genetics
    Humans
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85072993118&doi=10.1085%2fjgp.201912457&partnerID=40&md5=c1611dd8f9ac7ac7a72f77e97231096e; http://hdl.handle.net/10713/11156
    ae974a485f413a2113503eed53cd6c53
    10.1085/jgp.201912457
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