Dystonia caused by ANO3 variants is due to attenuated Ca influx by ORAI1.

Background: 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.

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

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

Conclusions: Dysregulated Ca 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.