• Effects of Single Nucleotide Polymorphisms in Human KCNMA1 on BK Current Properties

      Plante, A.E.; Lai, M.H.; Lu, J.; Meredith, A.L. (Frontiers Media S.A., 2019)
      BK Ca2+-activated K+ channels are important regulators of membrane excitability. Multiple regulatory mechanisms tailor BK current properties across tissues, such as alternative splicing, posttranslational modifications, and auxiliary subunits. Another potential mechanism for modulating BK channel activity is genetic variation due to single nucleotide polymorphisms (SNPs). The gene encoding the human BK α subunit, KCNMA1, contains hundreds of SNPs. However, the variation in BK channel activity due to SNPs is not well studied. Here, we screened the effects of four SNPs (A138V, C495G, N599D, and R800W) on BK currents in HEK293T cells, selected based on predicted protein pathogenicity or disease linkage. We found that the SNPs C495G and R800W had the largest effects on BK currents, affecting the conductance–voltage relationship across multiple Ca2+ conditions in the context of two BK channel splice variants. In symmetrical K+, C495G shifted the V1/2 to more hyperpolarized potentials (by −15 to −20 mV) and accelerated activation, indicating C495G confers some gain-of-function properties. R800W shifted the V1/2 to more depolarized potentials (+15 to +35 mV) and slowed activation, conferring loss-of-function properties. Moreover, the C495G and R800W effects on current properties were found to persist with posttranslational modifications. In contrast, A138V and N599D had smaller and more variable effects on current properties. Neither application of alkaline phosphatase to patches, which results in increased BK channel activity attributed to channel dephosphorylation, nor bidirectional redox modulations completely abrogated SNP effects on BK currents. Lastly, in physiological K+, C495G increased the amplitude of action potential (AP)-evoked BK currents, while R800W had a more limited effect. However, the introduction of R800W in parallel with the epilepsy-linked mutation D434G (D434G/R800W) decreased the amplitude of AP-evoked BK currents compared with D434G alone. These results suggest that in a physiological context, C495G could increase BK activation, while the effects of the loss-of-function SNP R800W could oppose the gain-of-function effects of an epilepsy-linked mutation. Together, these results implicate naturally occurring human genetic variation as a potential modifier of BK channel activity across a variety of conditions. Copyright 2019 Plante, Lai, Lu and Meredith.
    • An emerging spectrum of variants and clinical features in KCNMA1-linked channelopathy

      Miller, Jacob P; Moldenhauer, Hans J; Keros, Sotirios; Meredith, Andrea L (Taylor and Francis Inc., 2021-07-05)
      KCNMA1-linked channelopathy is an emerging neurological disorder characterized by heterogeneous and overlapping combinations of movement disorder, seizure, developmental delay, and intellectual disability. KCNMA1 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. In this review, we summarize 37 KCNMA1 alleles from 69 patients currently defining the channelopathy and assess key diagnostic and clinical hallmarks. At present, 3 variants are classified as gain-of-function with respect to BK channel activity, 14 loss-of-function, 15 variants of uncertain significance, and putative benign/VUS. Symptoms associated with these variants were curated from patient-provided information and prior publications to define the spectrum of clinical phenotypes. In this newly expanded cohort, seizures showed no differential distribution between patients harboring GOF and LOF variants, while movement disorders segregated by mutation type. Paroxysmal non-kinesigenic dyskinesia was predominantly observed among patients with GOF alleles of the BK channel, although not exclusively so, while additional movement disorders were observed in patients with LOF variants. Neurodevelopmental and structural brain abnormalities were prevalent in patients with LOF mutations. In contrast to mutations, disease-associated KCNMA1 single nucleotide polymorphisms were not predominantly related to neurological phenotypes but covered a wider set of peripheral physiological functions. Together, this review provides additional evidence exploring the genetic and biochemical basis for KCNMA1-linked channelopathy and summarizes the clinical repository of patient symptoms across multiple types of KCNMA1 gene variants.
    • Lisdexamfetamine Therapy in Paroxysmal Non-kinesigenic Dyskinesia Associated with the KCNMA1-N999S Variant

      Keros, Sotirios; Heim, Jennifer; Hakami, Wejdan; Zohar-Dayan, Efrat; Ben-Zeev, Bruria; Grinspan, Zach; Kruer, Michael C.; Meredith, Andrea L. (John Wiley and Sons Inc., 2021-01-01)
      Background: KCNMA1-linked channelopathy is a rare movement disorder first reported in 2005. Paroxysmal non-kinesigenic dyskinesia (PNKD) in KCNMA1-linked channelopathy is the most common symptom in patients harboring the KCNMA1-N999S mutation. PNKD episodes occur up to hundreds of times daily with significant morbidity and limited treatment options, often in the context of epilepsy. Cases: We report 6 cases with the KCNMA1-N999S variant treated with lisdexamfetamine (0.7–1.25 mg/kg/day), a pro-drug of dextroamphetamine. Data were collected retrospectively from interviews and chart review. Parent-reported daily PNKD episode counts were reduced under treatment, ranging from a 10-fold decrease to complete resolution. Conclusion: Our findings suggest that lisdexamfetamine is an effective therapy for PNKD3 (KCNMA1-associated PNKD). Treatment produced dramatic reductions in debilitating dyskinesia episodes, without provocation or exacerbation of other KCNMA1-associated symptoms such as seizures. © 2021 The Authors.
    • Status Dystonicus, Oculogyric Crisis and Paroxysmal Dyskinesia in a 25 Year-Old Woman with a Novel Variant, K457E.

      Buckley, Cliona; Williams, Jennifer; Munteanu, Tudor; King, Mary; Park, Su Mi; Meredith, Andrea L; Lynch, Timothy (Center for Digital Research and Scholarship, 2020-10-27)
      The diagnosis of a paroxysmal dyskinesia is difficult and status dystonicus is a rare life threatening movement disorder characterised by severe, frequent or continuous episodes of dystonic spasms. A 25 year old woman with chronic ataxia and paroxysmal dyskinesia presented with facial twitching, writhing of arms, oculogyric crisis and visual and auditory hallucinations. She developed respiratory failure and was ventilated. No cause was found so whole exome sequencing was performed and this revealed a novel, non-synonymous heterozygous variant in exon 11 of the KCNMA1 gene, K457E (c 1369A>G) in the patient but not her parents. This variant has not been previously reported in gnomAD or ClinVar. The finding of a de novo variant in a potassium channel gene guided a trial of the potassium channel antagonist 3,4 diaminopyridine resulting in significant improvement, discharge from the intensive care unit and ultimately home.