New research reveals that mutations in the ANO3 gene cause dystonia by disrupting calcium signaling and potassium channel activation in neurons, potentially opening new therapeutic avenues for this movement disorder.

In findings published in BMC Medicine, investigators demonstrated that ANO3 variants associated with dystonia significantly reduce the expression of ORAI1 calcium channels in cell membranes, leading to impaired calcium signaling and compromised activation of KCa3.1 potassium channels, which help regulate neuronal excitability.

The study examined four ANO3 variants (V561L, S651N, A599D, and S116L), identifying correlations between these mutations and clinical phenotypes, including early-onset dystonia, dyskinetic encephalopathy, and intellectual disabilities. For example, patients with V561L or S651N exhibited pronounced developmental delays and motor dysfunction, while those with S116L displayed milder symptoms​.

Variant-specific findings highlighted increased phospholipid scrambling and calcium sensitivity in V561L and S651N, with basal scrambling activity significantly elevated compared to wild-type ANO3 (e.g., >2-fold AnxV positivity in S651N, p < 0.05). This abnormal activity may predispose cells to damage and heightened excitability​.

The authors reported that these mutations inhibited store-operated calcium entry (SOCE) via ORAI1 channels, reducing calcium store filling in the endoplasmic reticulum (e.g., SOCE reductions of ~50% in V561L and S651N, p < 0.05) and impairing activation of KCa3.1 channels required for neuronal repolarization​.

"Dysregulated Ca²⁺ signaling by ANO3 variants may impair the activation of K⁺ channels in striatal neurons of the brain, thereby causing dystonia," wrote Karl Kunzelmann, MD, of the University of Regensburg, Germany, and colleagues.

These cellular studies provide key insights into disease mechanisms, but the authors emphasized the need for additional research. Transgenic animal models are required to fully understand how these mutations affect striatal neurons and validate the proposed pathogenic pathway.

Therapeutically, the study noted that riluzole, an activator of KCa3.1 channels, has shown promise in treating movement disorders and could be a potential treatment strategy for ANO3-related dystonia.

This work sheds light on the molecular basis of ANO3-related dystonia and identifies calcium signaling pathways and potassium channel function as potential therapeutic targets.

The study was supported by DFG Transregio-SFB Project-ID 509149993, TRR 374 (Project A3). The authors declared no competing interests.