Ousingsawat Jiraporn, Talbi Khaoula, Gómez-Martín Hilario, Koy Anne, Fernández-Jaén Alberto, Tekgül Hasan, Serdaroğlu Esra, Ortigoza-Escobar Juan Darío, Schreiber Rainer, Kunzelmann Karl
Physiological Institute, University of Regensburg, University Street 31, 93053, Regensburg, Germany.
Pediatric Neurology Unit, Department of Pediatrics, Hospital Universitario de Salamanca, 37007 Castillay , Leon, Spain.
BMC Med. 2025 Jan 7;23(1):12. doi: 10.1186/s12916-024-03839-5.
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, 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.
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.
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.
肌张力障碍是一种常见的神经运动亢进性疾病，可由磷脂翻转酶和离子通道anoctamin 3（ANO3，TMEM16C）的突变引起。我们之前报道过携带ANO3变异体S651N、V561L、A599D和S651N的杂合子患者，这些变异体通过未知机制导致肌张力障碍。
我们应用电生理学、钙测量和细胞生物学方法，分析携带ANO3变异体的杂合子患者中导致细胞内钙信号异常和钾通道激活缺陷的分子机制。
表达后，内质网钙库排空（储存释放），特别是储存性钙内流（SOCE）受到强烈抑制，导致钾（KCNN）通道激活受损，但钠激活钾通道（K；SLO2）不受影响。数据表明，在表达ANO3变异体的细胞的质膜中，储存性ORAI1钙内流通道的表达严重受损。
ANO3变异体导致的钙信号失调可能会损害大脑纹状体神经元中钾通道的激活，从而导致肌张力障碍。此外，数据首次表明ANO3可能像其他anoctamins一样对质膜中的蛋白质表达进行调控。
