Structural mapping of patient-associated KCNMA1 gene variants.

KCNMA1-linked channelopathy is a neurological disorder characterized by seizures, motor abnormalities, and neurodevelopmental disabilities. The disease mechanisms are predicted to result from alterations in KCNMA1-encoded BK K channel activity; however, only a subset of the patient-associated variants have been functionally studied. The localization of these variants within the tertiary structure or evaluation by pathogenicity algorithms has not been systematically assessed.

Structural mapping of patient-associated gene variants.

KCNMA1-linked channelopathy is a neurological disorder characterized by seizures, motor abnormalities, and neurodevelopmental disabilities. The disease mechanisms are predicted to result from alterations in KCNMA1-encoded BK channel activity; however, only a subset of the patient-associated variants have been functionally studied. The localization of these variants within the tertiary structure or evaluation by pathogenicity algorithms has not been systematically assessed.

Effect of an autism-associated variant, G124R, on BK channel properties.

BK K channels are critical regulators of neuron and muscle excitability, comprised of a tetramer of pore-forming αsubunits from the gene and cell- and tissue-selective β subunits (). Mutations in are associated with neurological disorders, including autism. However, little is known about the role of neuronal BK channel β subunits in human neuropathology.

BK channel properties correlate with neurobehavioral severity in three -linked channelopathy mouse models.

KCNMA1 forms the pore of BK K channels, which regulate neuronal and muscle excitability. Recently, genetic screening identified heterozygous variants in a subset of patients with debilitating paroxysmal non-kinesigenic dyskinesia, presenting with or without epilepsy (PNKD3). However, the relevance of mutations and the basis for clinical heterogeneity in PNKD3 has not been established.

An emerging spectrum of variants and clinical features in -linked channelopathy.

-linked channelopathy is an emerging neurological disorder characterized by heterogeneous and overlapping combinations of movement disorder, seizure, developmental delay, and intellectual disability. encodes the BK K channel, which contributes to both excitatory and inhibitory neuronal and muscle activity. Understanding the basis of the disorder is an important area of active investigation; however, the rare prevalence has hampered the development of large patient cohorts necessary to establish genotype-phenotype correlations.

Comparative gain-of-function effects of the -N999S mutation on human BK channel properties.

, encoding the voltage- and calcium-activated potassium channel, has a pivotal role in brain physiology. Mutations in are associated with epilepsy and/or dyskinesia (PNKD3). Two mutations correlated with these phenotypes, D434G and N999S, were previously identified as producing gain-of-function (GOF) effects on BK channel activity.

-linked channelopathy.

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.