Dystonia caused by ANO3 variants is due to attenuated Ca²⁺ influx by ORAI1

Dystonia is a common neurological hyperkinetic movement disorder that can be caused by mutations in anoctamin 3 (ANO3, TMEM16C), a phospholipid scramblase and ion channel. We previously reported patients that were heterozygous for the ANO3 variants S651N, V561L, A599D and S651N, which cause dystonia by unknown mechanisms.

We applied electrophysiology, Ca²⁺ measurements and cell biological methods to analyze the molecular mechanisms that lead to aberrant intracellular Ca²⁺ signals and defective activation of K⁺ channels in patients heterozygous for the ANO3 variants.

Upon expression, emptying of the endoplasmic reticulum Ca²⁺ store (store release) and particularly store-operated Ca²⁺ entry (SOCE) were strongly inhibited, leading to impaired activation of K_Ca3.1 (KCNN) K⁺ channels, but not of Na⁺-activated K⁺ channels (K_Na; SLO2). The data provide evidence for a strongly impaired expression of store-operated ORAI1 Ca²⁺ influx channels in the plasma membrane of cells expressing ANO3 variants.

Dysregulated Ca²⁺ signaling by ANO3 variants may impair the activation of K⁺ channels in striatal neurons of the brain, thereby causing dystonia. Furthermore, the data provide a first indication of a possible regulation of protein expression in the plasma membrane by ANO3, as has been described for other anoctamins.