Broadening the clinical spectrum: molecular mechanisms and new phenotypes of ANO3-dystonia

Basit Öğe Kaydı
dc.authoridOrtigoza-Escobar, Juan Dario/0000-0002-6320-2641
dc.authoridSERDAROGLU, ESRA/0000-0001-9925-0859
dc.authoridKunzelmann, Karl/0000-0001-6222-4593
dc.authoridOusingsawat, Dr.Jiraporn/0000-0003-4318-2601
dc.authoridFernandez-Jaen, Alberto/0000-0003-3306-9832
dc.contributor.authorOusingsawat, Jiraporn
dc.contributor.authorTalbi, Khaoula
dc.contributor.authorGomez-Martin, Hilario
dc.contributor.authorKoy, Anne
dc.contributor.authorFernandez-Jaen, Alberto
dc.contributor.authorTekgul, Hasan
dc.contributor.authorSerdaroglu, Esra
dc.date.accessioned2024-08-31T07:48:08Z
dc.date.available2024-08-31T07:48:08Z
dc.date.issued2024
dc.departmentEge Üniversitesien_US
dc.description.abstractAnoctamin 3 (ANO3) belongs to a family of transmembrane proteins that form phospholipid scramblases and ion channels. A large number of ANO3 variants were identified as the cause of craniocervical dystonia, but the underlying pathogenic mechanisms remain obscure. It was suggested that ANO3 variants may dysregulate intracellular Ca2+ signalling, as variants in other Ca2+ regulating proteins like hippocalcin were also identified as a cause of dystonia. In this study, we conducted a comprehensive evaluation of the clinical, radiological and molecular characteristics of four individuals from four families who carried heterozygous variants in ANO3. The median age at follow-up was 6.6 years (ranging from 3.8 to 8.7 years). Three individuals presented with hypotonia and motor developmental delay. Two patients exhibited generalized progressive dystonia, while one patient presented with paroxysmal dystonia. Additionally, another patient exhibited early dyskinetic encephalopathy. One patient underwent bipallidal deep brain stimulation (DBS) and showed a mild but noteworthy response, while another patient is currently being considered for DBS treatment. Neuroimaging analysis of brain MRI studies did not reveal any specific abnormalities. The molecular spectrum included two novel ANO3 variants (V561L and S116L) and two previously reported ANO3 variants (A599D and S651N). As anoctamins are suggested to affect intracellular Ca2+ signals, we compared Ca2+ signalling and activation of ion channels in cells expressing wild-type ANO3 and cells expressing anoctamin variants. Novel V561L and S116L variants were compared with previously reported A599D and S651N variants and with wild-type ANO3 expressed in fibroblasts isolated from patients or when overexpressed in HEK293 cells. We identified ANO3 as a Ca2+-activated phospholipid scramblase that also conducts ions. Impaired Ca2+ signalling and compromised activation of Ca2+-dependent K+ channels were detected in cells expressing ANO3 variants. In the brain striatal cells of affected patients, impaired activation of KCa3.1 channels due to compromised Ca2+ signals may lead to depolarized membrane voltage and neuronal hyperexcitability and may also lead to reduced cellular viability, as shown in the present study. In conclusion, our study reveals the association between ANO3 variants and paroxysmal dystonia, representing the first reported link between these variants and this specific dystonic phenotype. We demonstrate that ANO3 functions as a Ca2+-activated phospholipid scramblase and ion channel; cells expressing ANO3 variants exhibit impaired Ca2+ signalling and compromised activation of Ca2+-dependent K+ channels. These findings provide a mechanism for the observed clinical manifestations and highlight the importance of ANO3 for neuronal excitability and cellular viability.en_US
dc.description.sponsorshipDeutsche Forschungsgemeinschaften_US
dc.description.sponsorshipSupported by Deutsche Forschungsgemeinschaft. #Transregio-SFB TRR364 (Projekt A3).en_US
dc.identifier.doi10.1093/brain/awad412
dc.identifier.endpage1995en_US
dc.identifier.issn0006-8950
dc.identifier.issn1460-2156
dc.identifier.issue6en_US
dc.identifier.pmid38079528en_US
dc.identifier.scopus2-s2.0-85195051416en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.startpage1982en_US
dc.identifier.urihttps://doi.org/10.1093/brain/awad412
dc.identifier.urihttps://hdl.handle.net/11454/104677
dc.identifier.volume147en_US
dc.identifier.wosWOS:001214294900001en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.indekslendigikaynakPubMeden_US
dc.language.isoenen_US
dc.publisherOxford Univ Pressen_US
dc.relation.ispartofBrainen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/closedAccessen_US
dc.snmz20240831_Uen_US
dc.subjectDystoniaen_US
dc.subjectTmem16cen_US
dc.subjectAnoctamin 3en_US
dc.subjectAno3en_US
dc.subjectCa2+ Signallingen_US
dc.subjectK+ Channelsen_US
dc.titleBroadening the clinical spectrum: molecular mechanisms and new phenotypes of ANO3-dystoniaen_US
dc.typeArticleen_US

Dosyalar

Koleksiyon

WoS İndeksli Yayınlar Koleksiyonu
PubMed İndeksli Yayın Koleksiyonu
Scopus İndeksli Yayınlar Koleksiyonu