Müller, Marion

[["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Basic Research in Cardiology"],["dc.bibliographiccitation.volume","117"],["dc.contributor.author","Kokot, Karoline E."],["dc.contributor.author","Kneuer, Jasmin M."],["dc.contributor.author","John, David"],["dc.contributor.author","Rebs, Sabine"],["dc.contributor.author","Möbius-Winkler, Maximilian N."],["dc.contributor.author","Erbe, Stephan"],["dc.contributor.author","Müller, Marion"],["dc.contributor.author","Andritschke, Michael"],["dc.contributor.author","Gaul, Susanne"],["dc.contributor.author","Sheikh, Bilal N."],["dc.contributor.author","Boeckel, Jes-Niels"],["dc.date.accessioned","2022-07-01T07:35:35Z"],["dc.date.available","2022-07-01T07:35:35Z"],["dc.date.issued","2022"],["dc.description.abstract","Abstract Alterations of RNA editing that affect the secondary structure of RNAs can cause human diseases. We therefore studied RNA editing in failing human hearts. Transcriptome sequencing showed that adenosine-to-inosine (A-to-I) RNA editing was responsible for 80% of the editing events in the myocardium. Failing human hearts were characterized by reduced RNA editing. This was primarily attributable to Alu elements in introns of protein-coding genes. In the failing left ventricle, 166 circRNAs were upregulated and 7 circRNAs were downregulated compared to non-failing controls. Most of the upregulated circRNAs were associated with reduced RNA editing in the host gene. ADAR2, which binds to RNA regions that are edited from A-to-I, was decreased in failing human hearts. In vitro , reduction of ADAR2 increased circRNA levels suggesting a causal effect of reduced ADAR2 levels on increased circRNAs in the failing human heart. To gain mechanistic insight, one of the identified upregulated circRNAs with a high reduction of editing in heart failure, AKAP13, was further characterized. ADAR2 reduced the formation of double-stranded structures in AKAP13 pre-mRNA, thereby reducing the stability of Alu elements and the circularization of the resulting circRNA. Overexpression of circAKAP13 impaired the sarcomere regularity of human induced pluripotent stem cell-derived cardiomyocytes. These data show that ADAR2 mediates A-to-I RNA editing in the human heart. A-to-I RNA editing represses the formation of dsRNA structures of Alu elements favoring canonical linear mRNA splicing and inhibiting the formation of circRNAs. The findings are relevant to diseases with reduced RNA editing and increased circRNA levels and provide insights into the human-specific regulation of circRNA formation."],["dc.description.sponsorship"," Deutsche Gesellschaft für Kardiologie-Herz und Kreislaufforschung. http://dx.doi.org/10.13039/501100010578"],["dc.description.sponsorship"," Deutsche Forschungsgemeinschaft http://dx.doi.org/10.13039/501100001659"],["dc.description.sponsorship"," Universität Leipzig 501100008678"],["dc.identifier.doi","10.1007/s00395-022-00940-9"],["dc.identifier.pii","940"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/112209"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-581"],["dc.relation.eissn","1435-1803"],["dc.relation.issn","0300-8428"],["dc.rights.uri","https://creativecommons.org/licenses/by/4.0"],["dc.title","Reduction of A-to-I RNA editing in the failing human heart regulates formation of circular RNAs"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.artnumber","12230"],["dc.bibliographiccitation.firstpage","12230"],["dc.bibliographiccitation.issue","20"],["dc.bibliographiccitation.journal","International Journal of Molecular Sciences"],["dc.bibliographiccitation.volume","23"],["dc.contributor.affiliation","Sedaghat-Hamedani, Farbod; 1Institute for Cardiomyopathies Heidelberg (ICH), University Hospital Heidelberg, 69120 Heidelberg, Germany"],["dc.contributor.affiliation","Rebs, Sabine; 4Department of Cardiology and Pneumology, Georg-August-University Göttingen, 37073 Göttingen, Germany"],["dc.contributor.affiliation","Kayvanpour, Elham; 1Institute for Cardiomyopathies Heidelberg (ICH), University Hospital Heidelberg, 69120 Heidelberg, Germany"],["dc.contributor.affiliation","Zhu, Chenchen; 7Department of Genetics, Stanford University, Stanford, CA 94305, USA"],["dc.contributor.affiliation","Amr, Ali; 1Institute for Cardiomyopathies Heidelberg (ICH), University Hospital Heidelberg, 69120 Heidelberg, Germany"],["dc.contributor.affiliation","Müller, Marion; 1Institute for Cardiomyopathies Heidelberg (ICH), University Hospital Heidelberg, 69120 Heidelberg, Germany"],["dc.contributor.affiliation","Haas, Jan; 1Institute for Cardiomyopathies Heidelberg (ICH), University Hospital Heidelberg, 69120 Heidelberg, Germany"],["dc.contributor.affiliation","Wu, Jingyan; 7Department of Genetics, Stanford University, Stanford, CA 94305, USA"],["dc.contributor.affiliation","Steinmetz, Lars M.; 2DZHK (German Centre for Cardiovascular Research), Partner Site Heidelberg and Mannheim, 69120 Heidelberg, Germany"],["dc.contributor.affiliation","Ehlermann, Philipp; 1Institute for Cardiomyopathies Heidelberg (ICH), University Hospital Heidelberg, 69120 Heidelberg, Germany"],["dc.contributor.affiliation","Streckfuss-Bömeke, Katrin; 4Department of Cardiology and Pneumology, Georg-August-University Göttingen, 37073 Göttingen, Germany"],["dc.contributor.affiliation","Frey, Norbert; 1Institute for Cardiomyopathies Heidelberg (ICH), University Hospital Heidelberg, 69120 Heidelberg, Germany"],["dc.contributor.affiliation","Meder, Benjamin; 1Institute for Cardiomyopathies Heidelberg (ICH), University Hospital Heidelberg, 69120 Heidelberg, Germany"],["dc.contributor.author","Sedaghat-Hamedani, Farbod"],["dc.contributor.author","Rebs, Sabine"],["dc.contributor.author","Kayvanpour, Elham"],["dc.contributor.author","Zhu, Chenchen"],["dc.contributor.author","Amr, Ali"],["dc.contributor.author","Müller, Marion"],["dc.contributor.author","Haas, Jan"],["dc.contributor.author","Wu, Jingyan"],["dc.contributor.author","Steinmetz, Lars M."],["dc.contributor.author","Ehlermann, Philipp"],["dc.contributor.author","Meder, Benjamin"],["dc.contributor.editor","Chandra Janga, Sarath"],["dc.date.accessioned","2022-12-01T08:31:40Z"],["dc.date.available","2022-12-01T08:31:40Z"],["dc.date.issued","2022"],["dc.date.updated","2022-11-11T13:12:19Z"],["dc.description.abstract","Dilated cardiomyopathy (DCM) is a common cause of heart failure (HF) and is of familial origin in 20–40% of cases. Genetic testing by next-generation sequencing (NGS) has yielded a definite diagnosis in many cases; however, some remain elusive. In this study, we used a combination of NGS, human-induced pluripotent-stem-cell-derived cardiomyocytes (iPSC-CMs) and nanopore long-read sequencing to identify the causal variant in a multi-generational pedigree of DCM. A four-generation family with familial DCM was investigated. Next-generation sequencing (NGS) was performed on 22 family members. Skin biopsies from two affected family members were used to generate iPSCs, which were then differentiated into iPSC-CMs. Short-read RNA sequencing was used for the evaluation of the target gene expression, and long-read RNA nanopore sequencing was used to evaluate the relevance of the splice variants. The pedigree suggested a highly penetrant, autosomal dominant mode of inheritance. The phenotype of the family was suggestive of laminopathy, but previous genetic testing using both Sanger and panel sequencing only yielded conflicting evidence for LMNA p.R644C (rs142000963), which was not fully segregated. By re-sequencing four additional affected family members, further non-coding LMNA variants could be detected: rs149339264, rs199686967, rs201379016, and rs794728589. To explore the roles of these variants, iPSC-CMs were generated. RNA sequencing showed the LMNA expression levels to be significantly lower in the iPSC-CMs of the LMNA variant carriers. We demonstrated a dysregulated sarcomeric structure and altered calcium homeostasis in the iPSC-CMs of the LMNA variant carriers. Using targeted nanopore long-read sequencing, we revealed the biological significance of the variant c.356+1G>A, which generates a novel 5′ splice site in exon 1 of the cardiac isomer of LMNA, causing a nonsense mRNA product with almost complete RNA decay and haploinsufficiency. Using novel molecular analysis and nanopore technology, we demonstrated the pathogenesis of the rs794728589 (c.356+1G>A) splice variant in LMNA. This study highlights the importance of precise diagnostics in the clinical management and workup of cardiomyopathies."],["dc.identifier.doi","10.3390/ijms232012230"],["dc.identifier.pii","ijms232012230"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/118233"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-621"],["dc.publisher","MDPI"],["dc.relation.eissn","1422-0067"],["dc.rights","Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/)."],["dc.title","Genotype Complements the Phenotype: Identification of the Pathogenicity of an LMNA Splice Variant by Nanopore Long-Read Sequencing in a Large DCM Family"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]

[["dc.bibliographiccitation.firstpage","129"],["dc.bibliographiccitation.issue","1"],["dc.bibliographiccitation.journal","Genomics, Proteomics & Bioinformatics"],["dc.bibliographiccitation.lastpage","146"],["dc.bibliographiccitation.volume","20"],["dc.contributor.author","Boeckel, Jes-Niels"],["dc.contributor.author","Möbius-Winkler, Maximilian"],["dc.contributor.author","Müller, Marion"],["dc.contributor.author","Rebs, Sabine"],["dc.contributor.author","Eger, Nicole"],["dc.contributor.author","Schoppe, Laura"],["dc.contributor.author","Tappu, Rewati"],["dc.contributor.author","Kokot, Karoline E."],["dc.contributor.author","Kneuer, Jasmin M."],["dc.contributor.author","Gaul, Susanne"],["dc.contributor.author","Meder, Benjamin"],["dc.date.accessioned","2022-12-01T08:30:36Z"],["dc.date.available","2022-12-01T08:30:36Z"],["dc.date.issued","2022"],["dc.description.sponsorship"," http://dx.doi.org/10.13039/501100003042 Else Kroner-Fresenius-Stiftung"],["dc.description.sponsorship"," http://dx.doi.org/10.13039/501100004937 BMBF Berlin"],["dc.description.sponsorship"," http://dx.doi.org/10.13039/501100005970 Deutsche Stiftung für Herzforschung"],["dc.description.sponsorship"," http://dx.doi.org/10.13039/501100007316 Klaus Tschira Foundation"],["dc.description.sponsorship"," http://dx.doi.org/10.13039/501100013811 University of Leipzig Faculty of Medicine"],["dc.description.sponsorship"," http://dx.doi.org/10.13039/100010447 DZHK"],["dc.description.sponsorship"," http://dx.doi.org/10.13039/100011272 European Commission Seventh Framework Programme for Research and Technological Development Health"],["dc.identifier.doi","10.1016/j.gpb.2021.01.006"],["dc.identifier.pii","S1672022921001467"],["dc.identifier.uri","https://resolver.sub.uni-goettingen.de/purl?gro-2/117929"],["dc.language.iso","en"],["dc.notes.intern","DOI-Import GROB-621"],["dc.relation.issn","1672-0229"],["dc.rights.uri","https://www.elsevier.com/tdm/userlicense/1.0/"],["dc.title","SLM2 Is A Novel Cardiac Splicing Factor Involved in Heart Failure due to Dilated Cardiomyopathy"],["dc.type","journal_article"],["dc.type.internalPublication","yes"],["dspace.entity.type","Publication"]]