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

• Published in: BMC medicine Vol. 23; no. 1; pp. 1 - 12
• Main Authors: Ousingsawat, Jiraporn, Talbi, Khaoula, Gómez-Martín, Hilario, Koy, Anne, Fernández-Jaén, Alberto, Tekgül, Hasan, Serdaroğlu, Esra, Ortigoza-Escobar, Juan Darío, Schreiber, Rainer, Kunzelmann, Karl
• Format: Journal Article
• Language: English
• Published: London BioMed Central Ltd 07.01.2025; BioMed Central; BMC
• Subjects: Analysis; ANO3; Anoctamin 3; Apoptosis; Biological effects; Brain; Ca2+ signaling; Calcium (intracellular); Calcium (reticular); Calcium channels; Calcium influx; Calcium ions; Calcium signalling; Care and treatment; Cell activation; Cell death; Diagnosis; Dystonia; Electrophysiology; Endoplasmic reticulum; Fibroblasts; Flow cytometry; Genetic aspects; Genetic variation; Genotype & phenotype; Glucose; Health aspects; Ion channels; K+ channels; Membranes; Molecular modelling; Neostriatum; Orai1 protein; Patients; Phospholipids; Software; Statistical analysis; TMEM16C; Germany; United States > US
• ISSN: 1741-7015; 1741-7015
• DOI: 10.1186/s12916-024-03839-5

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.sup.2+ measurements and cell biological methods to analyze the molecular mechanisms that lead to aberrant intracellular Ca.sup.2+ signals and defective activation of K.sup.+ channels in patients heterozygous for the ANO3 variants. Results Upon expression, emptying of the endoplasmic reticulum Ca.sup.2+ store (store release) and particularly store-operated Ca.sup.2+ entry (SOCE) were strongly inhibited, leading to impaired activation of K.sub.Ca3.1 (KCNN) K.sup.+ channels, but not of Na.sup.+-activated K.sup.+ channels (K.sub.Na; SLO2). The data provide evidence for a strongly impaired expression of store-operated ORAI1 Ca.sup.2+ influx channels in the plasma membrane of cells expressing ANO3 variants. Conclusions Dysregulated Ca.sup.2+ signaling by ANO3 variants may impair the activation of K.sup.+ 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. Keywords: Dystonia, TMEM16C, Anoctamin 3, ANO3, Ca.sup.2+ signaling, K.sup.+ channels