In an assessment of families with familial atrial fibrillation, a complex KCNMA1 variant was identified in 1 kindred; the original identified individual also developed features of tachy-brady syndrome. KCNMA1 encodes a large conductance, voltage and calcium-sensitive potassium channel (BK or MaxiK channel). KCNMA1 has been implicated in multiple neurological diseases (see MIM:600150). There is a single orthologous gene in Drosophila, slo, for which multiple genetic reagents have been generated, including loss-of-function mutations, overexpression and RNAi targeting constructs, and alleles caused by insertional mutagenesis. Dmel\slo is also orthologous to the related human gene KCNU1.
Multiple UAS constructs of the human Hsap\KCNMA1 gene have been introduced into flies, including wild-type and the newly identified variant implicated in this disease. Cardiac-specific overexpression of the wild-type human KCNMA1 is unable to ameliorate the phenotypes of flies with slo deficiency. However, in the same slo[-]background, cardiac-specific overexpression of the human KCNMA1 disease-implicated variant exacerbates the slo[-] phenotypes, resulting in a significantly longer heart period compared with cardiac-specific overexpression of the wild-type human KCNMA1.
At 3 weeks post-eclosion, animals with amorphic genotypes of Dmel\slo exhibit increased heart period and a higher arrhythmia index compared to controls. Targeted knockdown of slo in the developing heart or in the adult heart results in a slower heartbeat and substantial arrhythmia. The presence of 1 or 2 extra copies of genomic slo in a wild-type fly background also markedly increases the heart period. Thus, heart rate regulation in flies appears sensitive to slo dose, with both deficiency and excess resulting in bradycardia.
Several other diseases postulated to be associated with KCNMA1 have been studied in flies: see 'paroxysmal nonkinesigenic dyskinesia, 3, with or without generalized epilepsy' (FBhh0001355) and 'alcohol, response to, KCNMA1-related' (FBhh0000683).
[updated May 2021 by FlyBase; FBrf0222196]
The term "arrhythmia" refers to any change from the normal sequence of electrical impulses in the heart, such as atrial fibrillation, bradycardia (slow heartbeat), tachycardia (rapid heart rate), conduction disorders, rhythm disorders, ventricular fibrillation, premature contractions. Arrhythmias may be completely harmless or life-threatening. (http://www.heart.org/HEARTORG/Conditions/Arrhythmia/AboutArrhythmia/About-Arrhythmia_UCM_002010_Article.jsp)
MaxiK channels are large conductance, voltage and calcium-sensitive potassium channels which are fundamental to the control of smooth muscle tone and neuronal excitability. MaxiK channels can be formed by 2 subunits: the pore-forming alpha subunit, which is the product of the KCNMA1 gene, and the modulatory beta subunit. Intracellular calcium regulates the physical association between the alpha and beta subunits. [Gene Cards, KCNMA1; 2021.05.16]
The large-conductance voltage- and Ca(2+)-activated K+ channel, also called the BK channel, differs from other K+ channels in that it can be activated by both intracellular Ca(2+) ions and by membrane depolarization. The BK channel consists of 4 alpha subunits and 4 optional auxiliary beta subunits. The pore-forming alpha subunit is encoded by the KCNMA1 gene, which produces multiple isoforms through alternative splicing. The 4 beta subunits are encoded by different genes that show tissue-specific expression (Sausbier et al., 2004; pubmed:15194823). [from MIM:600150; 2021.05.23]
Many to one: 2 human genes to 1 Drosophila gene.
High-scoring ortholog of human KCNMA1; moderate-scoring ortholog of human KCNU1 (1 Drosophila to 2 human). Dmel\slo shares 52% identity and 64% similarity with the human KCNMA1 gene.
