Details

Autor(en) / Beteiligte

• Bailey, Cole S
• Moldenhauer, Hans J
• Park, Su Mi
• Keros, Sotirios
• Meredith, Andrea L

Titel

KCNMA1 -linked channelopathy

Ist Teil von

• The Journal of general physiology, 2019-10, Vol.151 (10), p.1173-1189

Ort / Verlag

United States: Rockefeller University Press

Erscheinungsjahr

2019

Quelle

EZB-FREE-00999 freely available EZB journals

Beschreibungen/Notizen

• 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 ( ) 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 mutations identified in 37 patients dating back to 2005, with an array of clinically defined pathological phenotypes collectively referred to as " -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 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 mutations has expanded but remains primarily defined by brain and muscle dysfunction. Emerging evidence suggests the functional BK channel alterations produced by different 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 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 -linked channelopathy highlights the importance of better understanding the roles BK channels play in regulating cell excitability. Establishing causality between -linked BK channel dysfunction and specific patient symptoms may reveal new treatment approaches with the potential to increase therapeutic efficacy over current standard regimens.