Families with AF show an excess of rare functional K(+) channel gene variants of varying phenotypic effect size that may contribute to an atrial arrhythmogenic substrate. Atrial cell modeling is a useful tool to assess epistatic interactions between multiple variants.
Background
-
KCNMA1
encodes the α-subunit of the large-conductance Ca
2+
-activated K
+
channel, K
Ca
1.1, and lies within a linkage interval for atrial fibrillation (AF). Insights into the cardiac functions of K
Ca
1.1 are limited and
KCNMA1
has not been investigated as an AF candidate gene.
Methods
- The
KCNMA1
gene was sequenced in 118 patients with familial AF. The role of K
Ca
1.1 in normal cardiac structure and function was evaluated in humans, mice, zebrafish, and fly. A novel
KCNMA1
variant was functionally characterized.
Results
- A complex
KCNMA1
variant was identified in one kindred with AF. To evaluate potential disease mechanisms, we first evaluated the distribution of K
Ca
1.1 in normal hearts using immunostaining and immunogold electron microscopy. K
Ca
1.1 was seen throughout the atria and ventricles in humans and mice, with strong expression in the sinus node. In an ex vivo murine sinoatrial node preparation, addition of the K
Ca
1.1 antagonist, paxilline, blunted the increase in beating rate induced by adrenergic receptor stimulation. Knockdown of the K
Ca
1.1 ortholog,
kcnma1b
, in zebrafish embryos resulted in sinus bradycardia with dilatation and reduced contraction of the atrium and ventricle. Genetic inactivation of the
Drosophila
K
Ca
1.1 ortholog,
slo
, systemically or in adult stages, also slowed the heartbeat and produced fibrillatory cardiac contractions. Electrophysiological characterization of
slo
-deficient flies revealed bursts of action potentials, reflecting increased events of fibrillatory arrhythmias. Flies with cardiac-specific overexpression of the human
KCNMA1
mutant also showed increased heart period and bursts of action potentials, similar to the K
Ca
1.1 loss-of-function models.
Conclusions
- Our data point to a highly conserved role of K
Ca
1.1 in sinus node function in humans, mice, zebrafish and fly and suggest that K
Ca
1.1 loss of function may predispose to AF.
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