{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,2]],"date-time":"2025-11-02T10:42:54Z","timestamp":1762080174186,"version":"build-2065373602"},"reference-count":34,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2022,12,9]],"date-time":"2022-12-09T00:00:00Z","timestamp":1670544000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Food and Health Bureau, Hong Kong","award":["EH 472\/1-1","17111320","17106917"],"award-info":[{"award-number":["EH 472\/1-1","17111320","17106917"]}]},{"name":"Research Grants Council, Hong Kong","award":["EH 472\/1-1","17111320","17106917"],"award-info":[{"award-number":["EH 472\/1-1","17111320","17106917"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Rett syndrome (RTT) is a severe neurodevelopmental disorder caused by MeCP2 mutations. Nonetheless, the pathophysiological roles of MeCP2 mutations in the etiology of intrinsic cardiac abnormality and sudden death remain unclear. In this study, we performed a detailed functional studies (calcium and electrophysiological analysis) and RNA-sequencing-based transcriptome analysis of a pair of isogenic RTT female patient-specific induced pluripotent stem-cell-derived cardiomyocytes (iPSC-CMs) that expressed either MeCP2wildtype or MeCP2mutant allele and iPSC-CMs from a non-affected female control. The observations were further confirmed by additional experiments, including Wnt signaling inhibitor treatment, siRNA-based gene silencing, and ion channel blockade. Compared with MeCP2wildtype and control iPSC-CMs, MeCP2mutant iPSC-CMs exhibited prolonged action potential and increased frequency of spontaneous early after polarization. RNA sequencing analysis revealed up-regulation of various Wnt family genes in MeCP2mutant iPSC-CMs. Treatment of MeCP2mutant iPSC-CMs with a Wnt inhibitor XAV939 significantly decreased the \u03b2-catenin protein level and CACN1AC expression and ameliorated their abnormal electrophysiological properties. In summary, our data provide novel insight into the contribution of activation of the Wnt\/\u03b2-catenin signaling cascade to the cardiac abnormalities associated with MeCP2 mutations in RTT.<\/jats:p>","DOI":"10.3390\/ijms232415609","type":"journal-article","created":{"date-parts":[[2022,12,9]],"date-time":"2022-12-09T04:46:46Z","timestamp":1670561206000},"page":"15609","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Isogenic Human-Induced Pluripotent Stem-Cell-Derived Cardiomyocytes Reveal Activation of Wnt Signaling Pathways Underlying Intrinsic Cardiac Abnormalities in Rett Syndrome"],"prefix":"10.3390","volume":"23","author":[{"given":"Kwong-Man","family":"Ng","sequence":"first","affiliation":[{"name":"Cardiology Division, Department of Medicine, Li Ka-Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China"},{"name":"Center for Translational Stem Cell Biology, Hong Kong SAR, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qianqian","family":"Ding","sequence":"additional","affiliation":[{"name":"School of Life Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yiu-Lam","family":"Tse","sequence":"additional","affiliation":[{"name":"Cardiology Division, Department of Medicine, Li Ka-Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7058-4708","authenticated-orcid":false,"given":"Oscar Hou-In","family":"Chou","sequence":"additional","affiliation":[{"name":"Cardiology Division, Department of Medicine, Li Ka-Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wing-Hon","family":"Lai","sequence":"additional","affiliation":[{"name":"Cardiology Division, Department of Medicine, Li Ka-Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ka-Wing","family":"Au","sequence":"additional","affiliation":[{"name":"Cardiology Division, Department of Medicine, Li Ka-Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yee-Man","family":"Lau","sequence":"additional","affiliation":[{"name":"Cardiology Division, Department of Medicine, Li Ka-Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yue","family":"Ji","sequence":"additional","affiliation":[{"name":"Department of Surgery, Li Ka-Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chung-Wah","family":"Siu","sequence":"additional","affiliation":[{"name":"Cardiology Division, Department of Medicine, Li Ka-Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0265-2638","authenticated-orcid":false,"given":"Clara Sze-Man","family":"Tang","sequence":"additional","affiliation":[{"name":"Department of Surgery, Li Ka-Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China"},{"name":"Dr. Li Dak-Sum Research Centre, The University of Hong Kong, Hong Kong SAR, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alan","family":"Colman","sequence":"additional","affiliation":[{"name":"Harvard Department of Stem Cells and Regenerative Biology, Cambridge, MA 02138, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suk-Ying","family":"Tsang","sequence":"additional","affiliation":[{"name":"School of Life Sciences, The Chinese University of Hong Kong, Hong Kong SAR, China"},{"name":"State Key Laboratory of Agrobiotechnology, The Chinese University of Hong Kong, Hong Kong SAR, China"},{"name":"The Institute for Tissue Engineering and Regenerative Medicine (iTERM), The Chinese University of Hong Kong, Hong Kong SAR, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hung-Fat","family":"Tse","sequence":"additional","affiliation":[{"name":"Center for Translational Stem Cell Biology, Hong Kong SAR, China"},{"name":"Hong Kong-Guangdong Stem Cell and Regenerative Medicine Research Centre, The University of Hong Kong and Guangzhou Institutes of Biomedicine and Health, Hong Kong SAR, China"},{"name":"Heart and Vascular Center, The University of Hong Kong-Shenzhen Hospital, Shenzhen 518053, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1007\/s12017-014-8295-9","article-title":"Rett syndrome and MeCP2","volume":"16","author":"Liyanage","year":"2014","journal-title":"Neuromol. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1111\/j.1651-2227.1985.tb10993.x","article-title":"Rett\u2019s syndrome: Prevalence and impact on progressive severe mental retardation in girls","volume":"74","author":"Hagberg","year":"1985","journal-title":"Acta Paediatr. Scand."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/j.jpeds.2005.10.037","article-title":"Rett syndrome in Australia: A review of the epidemiology","volume":"148","author":"Laurvick","year":"2006","journal-title":"J. Pediatr."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1177\/0883073807307091","article-title":"Rett syndrome: Prevalence among Chinese and a comparison of MECP2 mutations of classic Rett syndrome with other neurodevelopmental disorders","volume":"22","author":"Wong","year":"2007","journal-title":"J. Child Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3377","DOI":"10.1007\/s10803-015-2519-1","article-title":"Brief report: Systematic review of Rett syndrome in males","volume":"45","author":"Reichow","year":"2015","journal-title":"J. Autism Dev. Disord."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1007\/s00246-004-0701-x","article-title":"Sudden death and cardiac arrhythmias in Rett syndrome","volume":"26","author":"Guideri","year":"2005","journal-title":"Pediatr. Cardiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"440","DOI":"10.1136\/adc.2005.090290","article-title":"Cardiac disease and Rett syndrome","volume":"91","author":"Acampa","year":"2006","journal-title":"Arch. Dis. Child."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"422","DOI":"10.1016\/j.neuron.2007.10.001","article-title":"The story of Rett syndrome: From clinic to neurobiology","volume":"56","author":"Chahrour","year":"2007","journal-title":"Neuron"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1038\/sj.cr.7290294","article-title":"Methyl-CpG binding proteins in the nervous system","volume":"15","author":"Fan","year":"2005","journal-title":"Cell Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1126\/science.1138389","article-title":"Reversal of neurological defects in a mouse model of Rett syndrome","volume":"315","author":"Guy","year":"2007","journal-title":"Science"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1038\/85899","article-title":"A mouse Mecp2-null mutation causes neurological symptoms that mimic Rett syndrome","volume":"27","author":"Guy","year":"2001","journal-title":"Nat. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1038\/85906","article-title":"Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice","volume":"27","author":"Chen","year":"2001","journal-title":"Nat. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/S0896-6273(02)00768-7","article-title":"Mice with truncated MeCP2 recapitulate many Rett syndrome features and display hyperacetylation of histone H3","volume":"35","author":"Shahbazian","year":"2002","journal-title":"Neuron"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"113ra125","DOI":"10.1126\/scitranslmed.3002982","article-title":"Pathogenesis of lethal cardiac arrhythmias in Mecp2 mutant mice: Implication for therapy in Rett syndrome","volume":"3","author":"McCauley","year":"2011","journal-title":"Sci. Transl. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"11204","DOI":"10.1038\/srep11204","article-title":"Disturbance of cardiac gene expression and cardiomyocyte structure predisposes Mecp2-null mice to arrhythmias","volume":"5","author":"Hara","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1016\/j.cell.2007.11.019","article-title":"Induction of pluripotent stem cells from adult human fibroblasts by defined factors","volume":"131","author":"Takahashi","year":"2007","journal-title":"Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/nbt1374","article-title":"Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts","volume":"26","author":"Nakagawa","year":"2008","journal-title":"Nat. Biotechnol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/j.stem.2011.06.004","article-title":"Unexpected X chromosome skewing during culture and reprogramming of human somatic cells can be alleviated by exogenous telomerase","volume":"9","author":"Pomp","year":"2011","journal-title":"Cell Stem Cell"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1419","DOI":"10.1007\/s00246-019-02151-x","article-title":"Long QT Syndrome: Genetics and Future Perspective","volume":"40","author":"Wallace","year":"2019","journal-title":"Pediatric Cardiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1926","DOI":"10.1002\/jcp.24642","article-title":"Primary cilium regulates CaV1.2 expression through Wnt signaling","volume":"229","author":"Muntean","year":"2014","journal-title":"J. Cell. Physiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1891","DOI":"10.1016\/j.hrthm.2010.09.017","article-title":"Early afterdepolarizations and cardiac arrhythmias","volume":"7","author":"Weiss","year":"2010","journal-title":"Heart Rhythm"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/j.conb.2019.07.002","article-title":"Genomic insights into MeCP2 function: A role for the maintenance of chromatin architecture","volume":"59","author":"Connolly","year":"2019","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1113\/JP276014","article-title":"Long QT syndrome caveolin-3 mutations differentially modulate Kv 4 and Cav 1.2 channels to contribute to action potential prolongation","volume":"597","author":"Tyan","year":"2019","journal-title":"J. Physiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1016\/j.yjmcc.2013.12.026","article-title":"Stimulation of ICa by basal PKA activity is facilitated by caveolin-3 in cardiac ventricular myocytes","volume":"68","author":"Bryant","year":"2014","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"472","DOI":"10.1016\/j.bbrc.2009.05.100","article-title":"Caveolin-3 negatively regulates recombinant cardiac KATP channels","volume":"385","author":"Garg","year":"2009","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1152\/physrev.00002.2005","article-title":"Molecular physiology of cardiac repolarization","volume":"85","author":"Nerbonne","year":"2005","journal-title":"Physiol. Rev."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1089\/cell.2010.0051","article-title":"ROCK inhibition facilitates the generation of human-induced pluripotent stem cells in a defined, feeder-, and serum-free system","volume":"12","author":"Lai","year":"2010","journal-title":"Cell Reprogram"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1373","DOI":"10.1161\/CIRCULATIONAHA.115.019847","article-title":"Amelioration of X-Linked Related Autophagy Failure in Danon Disease With DNA Methylation Inhibitor","volume":"134","author":"Ng","year":"2016","journal-title":"Circulation"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"H753","DOI":"10.1152\/ajpheart.00404.2012","article-title":"Processing and analysis of cardiac optical mapping data obtained with potentiometric dyes","volume":"303","author":"Laughner","year":"2012","journal-title":"Am. J. Physiol.-Heart Circ. Physiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1053\/j.gastro.2012.06.007","article-title":"Identification of PTK6, via RNA sequencing analysis, as a suppressor of esophageal squamous cell carcinoma","volume":"143","author":"Ma","year":"2012","journal-title":"Gastroenterology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/nmeth.1414","article-title":"Genome-scale DNA methylation mapping of clinical samples at single-nucleotide resolution","volume":"7","author":"Gu","year":"2010","journal-title":"Nat. Methods"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1093\/bib\/bbx013","article-title":"A survey of the approaches for identifying differential methylation using bisulfite sequencing data","volume":"19","author":"Shafi","year":"2018","journal-title":"Brief Bioinform."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1038\/nrg3273","article-title":"Analysing and interpreting DNA methylation data","volume":"13","author":"Bock","year":"2012","journal-title":"Nat. Rev. Genet."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1016\/j.molcel.2010.05.004","article-title":"Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities","volume":"38","author":"Heinz","year":"2010","journal-title":"Mol. 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