Background: Anoctamin 3 (ANO3) variants are linked to craniocervical dystonia, yet the underlying pathogenic mechanisms remain unclear. This study aims to comprehensively evaluate the clinical, radiological, and molecular characteristics of individuals with ANO3 variants.

Objectives: Investigate the impact of novel and reported ANO3 variants on intracellular Ca2+ signaling, K+ channels, and associated clinical manifestations, with a focus on paroxysmal dystonia.

Methods: Four individuals with ANO3 variants were examined clinically and molecularly. Neuroimaging and treatment responses, including deep brain stimulation (DBS), were assessed. Functional studies compared Ca2+ signaling and ion channel activation in cells expressing wild-type and variant ANO3.

Results: The median age at follow-up was 6.6 years. Clinical presentations varied, including hypotonia, motor delay, and generalized or paroxysmal dystonia. Two novel variants (V561L, S116L) and two reported variants (A599D, S651N) were identified. Neuroimaging revealed no specific abnormalities. DBS demonstrated a mild response in one patient. Functional studies showed impaired Ca2+ signaling and compromised K+ channel activation in cells expressing ANO3 variants.

Conclusion: This study establishes a link between ANO3 variants and paroxysmal dystonia, uncovering the role of ANO3 as a Ca2+-activated phospholipid scramblase and ion channel. Impaired Ca2+ signaling provides a mechanistic understanding of clinical manifestations, emphasizing the significance of ANO3 for neuronal excitability and cellular viability. These findings offer insights into potential therapeutic strategies for ANO3-associated dystonia.

Jiraporn Ousingsawat
University of Regensburg
Germany

Khaoula Talbi
University of Regensburg
Germany

Hilario Gómez-Martín
Hospital Universitario de Salamanca
Spain

Anne Koy
Faculty of Medicine and University Hospital Cologne
Germany

Alberto Fernández-Jaén
Hospital Universitario Quirónsalud
Spain

Hasan Tekgül
Ege Children's Hospital
Turkey

Esra Serdaroğlu
Gazi University
Turkey

Rainer Schreiber
University of Regensburg
Germany

Karl Kunzelmann
University of Regensburg
Germany

Juan Dario Ortigoza-Escobar
Hospital Sant Joan de Déu
Spain