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 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.

Status Dystonicus, Oculogyric Crisis and Paroxysmal Dyskinesia in a 25 Year-Old Woman with a Novel KCNMA1 Variant, K457E

“…Sixteen KCNMA1 variants in 37 symptomatic patients have been reported by Bailey et al [3]. Our patient's de novo variant (NM_001161352.2:c1369A>G; p.Lys457Glu) is novel and was not previously reported in the gnomAD (v2.1.1 and v3) or ClinVar databases.…”

“…Identifying the cause for status dystonicus can guide therapy. Our finding of a single, de novo variant in a potassium channel gene, previously associated with a hyperkinetic movement disorder [3] in our patient with paroxysmal dyskinesia, oculogyric crisis and status dystonicus suggests this residue substitution should be considered with respect to causation of her symptoms.…”

“…KCNMA1 encodes the alpha, pore-forming subunit of the calcium-sensitive potassium (BK) channel (OMIM: 600150) and is linked to the very rare autosomal dominant generalised epilepsy and paroxysmal non kinesigenic dyskinesia (OMIM: 609446 PNKD3) [3]. BK channels play an important role in neuronal excitability, passing outwards K + current upon membrane depolarization and increased intracellular Ca2+ during the action potential, generally leading to hyperpolarization of the membrane and decreased excitability [3]. They are involved in the regulation of excitability in smooth muscle, neurons, neuroendocrine tissues and neurotransmitter release [3,5].…”

“…BK channels play an important role in neuronal excitability, passing outwards K + current upon membrane depolarization and increased intracellular Ca2+ during the action potential, generally leading to hyperpolarization of the membrane and decreased excitability [3]. They are involved in the regulation of excitability in smooth muscle, neurons, neuroendocrine tissues and neurotransmitter release [3,5].…”

BK channels promote neuromuscular transmission

“…Elucidating the role of BK channels at NMJs could have important clinical implications (6). “Andrea Meredith and colleagues have recently identified patients with BK channel mutations and one of their clinical phenotypes is hypotonia,” Rich says.…”