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.

Identification and functional analysis of two new de novo KCNMA1 variants associated with Liang–Wang syndrome

“…Almost all of the identified genetic variants are clustered around the pore-forming S5-S6 segments and in the Ca 2+ sensing C-terminus. 17,18,20 In this study, we report four new patients with four different KCNMA1 variants, including two new de novo variants p.(A172T) and p.(A314T), and two previously reported variants of p.(N536H), and p.(N995S). We carefully characterized these variants by studying their functional effects on electrophysiological and biochemical characteristics of BK channels, and the spectrum of their associated clinical features (ie, genotype-phenotype correlation of the four variants).…”

“…(N449fs), p.(I663V), p.(P805L) and p.(D984N) 13,27 (Figure 6). Two reported mutations, p.(R458X) and p.(Y676Lfs*7), [15][16][17] were assumed to act by a LOF mechanism because of the stop codon change and frame-shift. However, we found a non-peer reviewed report in 'Research Square' stating that p.(R458X) acted by a GOF mechanism because the mutation increased potassium current in Michigan Cancer Foundation 7 (MCF 7) cells.…”

“…Interestingly, homozygous KCNMA1 variants were also reported, for example, p.(Y676Lfs*7) detected in two siblings with epilepsy, developmental delay and severe cerebellar atrophy, and p.(R458Ter) identified in a patient with paroxysmal dyskinesia, epilepsy, intellectual delay and corticospinal‐cerebellar tract atrophy 15,16 . To date, 19 pathogenic KCNMA1 variants have been reported to be associated with different neurological disorders in 42 patients 14,17‐20 . Three of them acted by GOF, nine by LOF and three without functional characterization.…”

“…Moreover, three KCNMA1 variants were identified in patients, but functional studies suggest that they are benign polymorphism that have no direct cause–consequence relationship with the disease. Almost all of the identified genetic variants are clustered around the pore‐forming S5‐S6 segments and in the Ca 2+ sensing C‐terminus 17,18,20 …”

“…15,16 To date, 19 pathogenic KCNMA1 variants have been reported to be associated with different neurological disorders in 42 patients. 14,[17][18][19][20] Three of them acted by GOF, nine by LOF and three without functional characterization. Moreover, three KCNMA1 variants were identified in patients, but functional studies suggest that they are benign polymorphism that have no direct cause-consequence relationship with the disease.…”