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The proposed pathogenic (TTTCA) pentanucleotide repeat expansion (exp) insertion, flanking the polymorphic (TTTTA)exp, has been reported in seven distinct FCMTE causative genes\/loci, and a repeat motif\u2010specific phenotype correlation is claimed. However, the pathogenic mechanism of FCMTE is still poorly understood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We investigated how the (TTTCA)exp insertion causes the disease, mainly employing the FCMTE1 patients\u2010induced pluripotent stem cell\u2010derived neurons (iPSC\u2010neurons),\u00a0focusing on the formation of (UUUCA)exp RNA foci and their associated cellular toxicity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>First, (TTTCA)exp insertion neither altered SAMD12 expression nor translates into repeat peptides. Second, (UUUCA)exp RNA foci were detected in both the constructed cell line and iPSC\u2010neurons, and presented toxicity effects. Third, NOVA2, a neuron\u2010specific splicing regulator, was identified as the key RNA\u2010binding protein interacting with (UUUCA)exp RNA. The (UUUCA)exp RNA disrupted the nuclear distribution pattern of NOVA2, and reciprocally, knockdown of NOVA2 promoted the formation of (UUUCA)exp RNA foci. Shared synaptic\u2010related pathways of alternative splicing events were observed in both FCMTE1\u2010iPSC\u2010neurons and NOVA target genes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These findings support a repeat motif\u2010dependent mechanism involving (UUUCA)exp RNA foci and the functional disruption of the key RNA\u2010binding protein NOVA2, providing valuable insights for future studies on FCMTE and other pentanucleotide repeat expansion diseases. \u00a9 2026 International Parkinson and Movement Disorder Society.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/mds.70270","type":"journal-article","created":{"date-parts":[[2026,3,19]],"date-time":"2026-03-19T02:50:21Z","timestamp":1773888621000},"page":"1479-1491","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["<scp>RNA<\/scp>\n                    Toxicity and Interacting\n                    <scp>RNA<\/scp>\n                    \u2010Binding Protein\n                    <scp>NOVA2<\/scp>\n                    of (\n                    <scp>UUUCA<\/scp>\n                    )exp\n                    <scp>RNA<\/scp>\n                    Foci in Familial Cortical Myoclonic Tremor with Epilepsy"],"prefix":"10.1002","volume":"41","author":[{"given":"Fan","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Neurology, The Second Affiliated Hospital Zhejiang University School of Medicine  Hangzhou China"},{"name":"Department of Neurology, Henan Provincial People's Hospital People's Hospital of Zhengzhou University  Zhengzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiling","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Second Affiliated Hospital Zhejiang University School of Medicine  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuqi","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Second Affiliated Hospital Zhejiang University School of Medicine  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haibin","family":"Xia","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Second Affiliated Hospital Zhejiang University School of Medicine  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiying","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Second Affiliated Hospital Zhejiang University School of Medicine  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-9940-9327","authenticated-orcid":false,"given":"Xinhui","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Second Affiliated Hospital Zhejiang University School of Medicine  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Second Affiliated Hospital Zhejiang University School of Medicine  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junfeng","family":"Ji","sequence":"additional","affiliation":[{"name":"Center of Stem Cell and Regenerative Medicine, School of Medicine Zhejiang University  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3155-5781","authenticated-orcid":false,"given":"Zhidong","family":"Cen","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Second Affiliated Hospital Zhejiang University School of Medicine  Hangzhou 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