KCNMA1-Linked Channelopathy

Abstract

KCNMA1 encodes the pore-forming α subunit of the ‘Big K+’ (BK) large conductance calcium and voltage-activated K+ channel (KCa1.1). BK channels are widely distributed across many tissues, including both excitable and non-excitable cells. Expression levels are highest in brain and muscle, where the 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 for BK channels in animal models, the consequences of dysfunctional BK channels in humans is 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.

Therapeutic effects of Chlorzoxazone, a BKCa channel agonist, in a mouse model of Fragile X syndrome

“…Recently, CHLOR has been shown exerting beneficial effects on the cognitive deficits and amyloid pathology in a mouse model of Alzheimer disease, by rescuing alterations in BKCa functionality and inflammatory imbalances (Bai & Ma, 2020). It is therefore possible that BKCa channels may represent a therapeutic target common to multiple disorders of the central nervous system (Bailey et al , 2019). This may be particularly interesting for neurodevelopmental disorders, as alterations in BKCa expression (in particular of the KCNMA1 major channel subunit) and functionality have been demonstrated in several of these pathologies (Bailey et al , 2019), including FXS and ASDs.…”

“…It is therefore possible that BKCa channels may represent a therapeutic target common to multiple disorders of the central nervous system (Bailey et al , 2019). This may be particularly interesting for neurodevelopmental disorders, as alterations in BKCa expression (in particular of the KCNMA1 major channel subunit) and functionality have been demonstrated in several of these pathologies (Bailey et al , 2019), including FXS and ASDs. The link between these two syndromes is largely supported (Hatton et al , 2006), as they are intertwined at the molecular (Darnell et al , 2011, Parikshak et al , 2013) and behavioural level (Bailey et al , 2001, Bailey et al , 1998, Brock & Hatton, 2010, Rogers et al , 2001): indeed, all FXS patients meet some aspects of the DSM criteria for ASD and at least 50% meet the full criteria (Roberts et al , 2007).…”

A Gain‐of‐Function Mutation in KCNMA1 Causes Dystonia Spells Controlled With Stimulant Therapy

“…BK, also known as Slo1 or K Ca 1.1 channel, is a special type of K + channel with dual sensitivity to membrane voltage and intracellular Ca 2+ 1‐5 . Consistent with its important physiological functions in neurons, 13 mutations of the KCNMA1 gene that encodes the BK pore‐forming α subunit have been identified in human patients 6‐12 . Only two have been reported as gain‐of‐function (GOF), and the others are loss‐of‐function mutations.…”

A 2020 View on the Genetics of Developmental and Epileptic Encephalopathies

“…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 ( CACNA1A , GRIN1 , SCN1B , and KCNMA1 ), 25 -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.…”