KCNMA1-linked channelopathy

Figures

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  Figure 1.. Human KCNMA1 mutations. Schematic of the KCNMA1 gene product, the α-subunit of the BK channel (GenBank accession no. NM_002247.3). The voltage-sensitive pore-forming region of the BK channel is comprised of transmembrane domains S0–S6, while the intracellular gating ring contains the two Ca2+ binding sites in the RCK1 and RCK2 domains. Red indicates GOF mutations (n = 2), blue indicates LOF or putative LOF mutations (n = 11), and black indicates putative benign mutations (n = 3) or VUS (n = 1). *C413Y/N499fs is a double mutation harbored by a single patient. Numbers to the right or left of each mutation indicate the total number of patients carrying each mutation reported in published studies. N995S, N999S, and N1053S are the same amino acid substitution, but are reported in the literature using three different reference sequencing number schemes.

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  Figure 2.. BK channel expression in human tissues and prominent phenotypes reported in patients with KCNMA1-linked channelopathy. Major tissues or systems expressing BK channels are depicted in black (high relative expression), gray (medium), and light gray (low). Organs demonstrating high levels of BK channel expression include the CNS (olfactory system, neocortex, basal ganglia, hippocampus, thalamus, habenula and its tract to the interpeduncular nucleus in the midbrain, cerebellum, vestibular nuclei in the hindbrain, and spinal cord), gastrointestinal tract (stomach, small intestine, and colon), and reproductive organs (corpus cavernosum, prostate, testes, ovaries, and uterus). Organs demonstrating medium BK channel expression include salivary glands, neuroendocrine glands (thyroid, parathyroid, adrenal), heart, urinary bladder, liver and gallbladder, kidneys, and spleen/immune system. Organs demonstrating low levels of BK channel include lungs, lymph nodes, vasculature, skeletal muscle, and bone. Data on expression levels were derived from the Human Protein Atlas v18.1 (https://www.proteinatlas.org; Uhlén et al., 2015), the NCBI Gene Database (https://www.ncbi.nlm.nih.gov), and…

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  Figure 3.. BK channel dysfunction by organ and functional system in rodent models. BK channel knockout mice (KCNMA1−/−) show a wider range of pathophysiology compared with human KCNMA1 patients with LOF mutations. Such findings are consistent with the extensive distribution of BK channels across tissues. Key organ and functional systems disrupted by BK channel dysfunction in mouse models are indicated. BK channel activity was required for several aspects of neurological operations in rodent models, such as regulation of neuronal excitability (Jin et al., 2000; Faber and Sah, 2003; Brenner et al., 2005; Shruti et al., 2008; Sheehan et al., 2009), ​locomotor function (Meredith et al., 2004; Sausbier et al., 2004; Chen et al., 2010), circadian rhythm (Meredith et al., 2006; Kent and Meredith, 2008; Montgomery et al., 2013; White et al., 2015; Whitt et al., 2016), learning and memory (Typlt et al., 2013b), vision (Henne and Jeserich, 2004; Grimes et al., 2009; Tanimoto et al., 2012), hearing and vestibular reflexes (Pyott et al., 2007; Maison et al., 2013; Rohmann et al., 2015; Pyott and Duncan, 2016; Nelson et al., 2017), and neurovascular coupling (Filosa et al., 2006; Girouard et al., 2010).…

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  Figure 4.. Patient phenotypes for GOF versus LOF KCNMA1 alleles. Summary of the main phenotypes exhibited by KCNMA1-linked channelopathy patients: seizure, movement disorder, neurodevelopment, and intellectual disability. The denominator is the total number of patients included in each mutation group, and the numerator is the number of patients reported with the particular phenotype. The intersection includes shared symptoms among all patients (n = 37) identified with any KCNMA1 mutation (n = 16) reported in this review. Additional subtype descriptors for PNKD, epilepsy, and sensory impairment are annotated. 11/20 of GOF patients had no additional description for their PNKD symptoms in the published reports.