KCNMA1-linked channelopathy

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 non-excitable 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 non-kinesigenic 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.

Depressed neuromuscular transmission causes weakness in mice lacking BK potassium channels

“…Our findings raise the possibility that motor dysfunction in patients with BK channel mutations ( Bailey et al, 2019 ) may be due in part to a presynaptic problem causing the failure of neuromuscular transmission. Lambert–Eaton myasthenic syndrome is another disorder where weakness is due to a reduction of presynaptic vesicle release ( Elmqvist and Lambert, 1968 ; Engisch et al, 1999 ).…”

“…The motor deficits include tremor, problems with gait, weak grip, and decreased ability to stay on the rotarod. In humans, mutations in the gene that encodes the BK channel ( KCNMA1 ) are linked with epilepsy, movement disorders, and hypotonia ( Bailey et al, 2019 ). Broadly, motor phenotypes caused by BK channel mutations or loss have been largely attributed to cerebellar dysfunction ( Meredith et al, 2004 ; Sausbier et al, 2004 ; Chen et al, 2010 ; Typlt et al, 2013 ).…”

A 2020 View on the Genetics of Developmental and Epileptic Encephalopathies

“…22,23 There are also an increasing number of case reports of biallelic pathogenic variants in genes more commonly associated with de novo variants ( Table 1). For most of these genes (CAC-NA1A, GRIN1, SCN1B, and KCNMA1), [25][26][27][28]30,31,38,39 the clinical presentation for individuals with AR variants is more severe than that of individuals with de novo variants. For 2 of these genes, CACNA1A and SCN1B, increased severity is likely due to the complete absence of functional channel versus haploinsufficiency in the instance of de novo variants.…”

BKCa Channels as Targets for Cardioprotection

“…BK Ca channels participate in a wide variety of fundamental physiological processes from vascular tone [ 11 , 12 ], cardiac rhythmicity [ 11 , 13 ], erectile and urinary autonomic functions [ 14 , 15 ], regulation of gene expression [ 6 ], and aging [ 16 ]. Recent reports suggest that alterations of BK Ca function and expression may associate with several pathological conditions, such as paroxysmal nonkinesigenic dyskinesia with a gain of function, and cerebellar ataxia with loss-of-function mutations [ 17 , 18 ], making them unique therapeutic targets. The exclusive initiative by the ‘ KCNMA1 channelopathy international advocacy foundation ’ has brought BK Ca -associated disorders to the forefront and facilitates education, treatment, and networking opportunities for KCNMA1 channelopathy patients, physicians, and researchers [ 19 ].…”

“…BK Ca channels with different subunit combinations can present a wide range of channel activity, rates of activation or deactivation, current rectification properties, and sensitivity to pharmacological agents [ 27 ]. When taking into consideration the number of splice variants and a plethora of combinations in which BK Ca channels can assemble, one can understand the functional diversity that is uniquely calibrated for the needs of a variety of cells in which they are expressed [ 4 , 5 , 10 , 17 ].…”