Dystonia caused by ANO3 variants is due to attenuated Ca2+ influx by ORAI1
Abstract 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,...
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BMC
2025-01-01
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| Online Access: | https://doi.org/10.1186/s12916-024-03839-5 |
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| author | Jiraporn Ousingsawat Khaoula Talbi Hilario Gómez-Martín Anne Koy Alberto Fernández-Jaén Hasan Tekgül Esra Serdaroğlu Juan Darío Ortigoza-Escobar Rainer Schreiber Karl Kunzelmann |
| author_facet | Jiraporn Ousingsawat Khaoula Talbi Hilario Gómez-Martín Anne Koy Alberto Fernández-Jaén Hasan Tekgül Esra Serdaroğlu Juan Darío Ortigoza-Escobar Rainer Schreiber Karl Kunzelmann |
| author_sort | Jiraporn Ousingsawat |
| collection | DOAJ |
| description | Abstract 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, Ca2+ measurements and cell biological methods to analyze the molecular mechanisms that lead to aberrant intracellular Ca2+ signals and defective activation of K+ channels in patients heterozygous for the ANO3 variants. Results Upon expression, emptying of the endoplasmic reticulum Ca2+ store (store release) and particularly store-operated Ca2+ entry (SOCE) were strongly inhibited, leading to impaired activation of KCa3.1 (KCNN) K+ channels, but not of Na+-activated K+ channels (KNa; SLO2). The data provide evidence for a strongly impaired expression of store-operated ORAI1 Ca2+ influx channels in the plasma membrane of cells expressing ANO3 variants. Conclusions Dysregulated Ca2+ 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. |
| format | Article |
| id | doaj-art-6babc2b2167c4ec0abed8d4bf71aa95e |
| institution | Kabale University |
| issn | 1741-7015 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
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| series | BMC Medicine |
| spelling | doaj-art-6babc2b2167c4ec0abed8d4bf71aa95e2025-01-12T12:26:51ZengBMCBMC Medicine1741-70152025-01-0123111210.1186/s12916-024-03839-5Dystonia caused by ANO3 variants is due to attenuated Ca2+ influx by ORAI1Jiraporn Ousingsawat0Khaoula Talbi1Hilario Gómez-Martín2Anne Koy3Alberto Fernández-Jaén4Hasan Tekgül5Esra Serdaroğlu6Juan Darío Ortigoza-Escobar7Rainer Schreiber8Karl Kunzelmann9Physiological Institute, University of RegensburgPhysiological Institute, University of RegensburgPediatric Neurology Unit, Department of Pediatrics, Hospital Universitario de SalamancaCentre for Rare Diseases, Faculty of Medicineand , University Hospital Cologne, University of CologneDepartment of Pediatric Neurology, Hospital Universitario QuirónsaludDivision of Pediatric Neurology, Ege Children’s Hospital, Ege University Medical SchoolDepartment of Pediatric Neurology, Gazi UniversityMovement Disorders Unit, Pediatric Neurology Department, Institut de Recerca Hospital Sant Joan de Déu BarcelonaPhysiological Institute, University of RegensburgPhysiological Institute, University of RegensburgAbstract 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, Ca2+ measurements and cell biological methods to analyze the molecular mechanisms that lead to aberrant intracellular Ca2+ signals and defective activation of K+ channels in patients heterozygous for the ANO3 variants. Results Upon expression, emptying of the endoplasmic reticulum Ca2+ store (store release) and particularly store-operated Ca2+ entry (SOCE) were strongly inhibited, leading to impaired activation of KCa3.1 (KCNN) K+ channels, but not of Na+-activated K+ channels (KNa; SLO2). The data provide evidence for a strongly impaired expression of store-operated ORAI1 Ca2+ influx channels in the plasma membrane of cells expressing ANO3 variants. Conclusions Dysregulated Ca2+ 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.https://doi.org/10.1186/s12916-024-03839-5DystoniaTMEM16CAnoctamin 3ANO3Ca2+ signalingK+ channels |
| spellingShingle | Jiraporn Ousingsawat Khaoula Talbi Hilario Gómez-Martín Anne Koy Alberto Fernández-Jaén Hasan Tekgül Esra Serdaroğlu Juan Darío Ortigoza-Escobar Rainer Schreiber Karl Kunzelmann Dystonia caused by ANO3 variants is due to attenuated Ca2+ influx by ORAI1 BMC Medicine Dystonia TMEM16C Anoctamin 3 ANO3 Ca2+ signaling K+ channels |
| title | Dystonia caused by ANO3 variants is due to attenuated Ca2+ influx by ORAI1 |
| title_full | Dystonia caused by ANO3 variants is due to attenuated Ca2+ influx by ORAI1 |
| title_fullStr | Dystonia caused by ANO3 variants is due to attenuated Ca2+ influx by ORAI1 |
| title_full_unstemmed | Dystonia caused by ANO3 variants is due to attenuated Ca2+ influx by ORAI1 |
| title_short | Dystonia caused by ANO3 variants is due to attenuated Ca2+ influx by ORAI1 |
| title_sort | dystonia caused by ano3 variants is due to attenuated ca2 influx by orai1 |
| topic | Dystonia TMEM16C Anoctamin 3 ANO3 Ca2+ signaling K+ channels |
| url | https://doi.org/10.1186/s12916-024-03839-5 |
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