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The pathogenesis of AOA1 remains unclear. The purpose of this study was to investigate the pathogenesis of a novel mutation, p.H201P\/H201R, carried by our AOA1 patient and the mechanism of AOA1 in an induced pluripotent stem cells (iPSCs) model. We edited iPSCs derived from a healthy individual to carry the\n                    <jats:italic>APTX<\/jats:italic>\n                    homozygous mutation p.H201P (H201P-iPSCs) or p.H201R (H201R-iPSCs) via CRISPR\/Cas9. We found that aprataxin expression was absent in both H201P- and H201R-iPSCs. The capacity of these\n                    <jats:italic>APTX<\/jats:italic>\n                    -mutant iPSCs to differentiate into neural progenitor cells (NPCs) and mature neurons was diminished. We observed an increase in DNA single-strand breaks (SSB) via a comet assay and poly(ADP-ribose) staining, and an increase in the ratio of cleaved PARP-1\/total PARP-1 in\n                    <jats:italic>APTX<\/jats:italic>\n                    -mutant NPCs and early immature neurons (EiNs), in addition of a heightened sensitivity to tert-butyl hydroperoxide in\n                    <jats:italic>APTX<\/jats:italic>\n                    -mutant EiNs. Moreover, a decrease of APE1 expression was observed in\n                    <jats:italic>APTX<\/jats:italic>\n                    -mutant NPCs and H201R-EiNs during neural differentiation. Our study established a practical iPSCs model to investigate AOA1 disease. We found that mutant aprataxin leads to defective neural differentiation, accompanied by the accumulation of DNA SSBs with increased cleaved PARP-1 and reduced APE1 expression of the base excision repair pathway.\n                  <\/jats:p>","DOI":"10.1038\/s41420-025-02723-2","type":"journal-article","created":{"date-parts":[[2025,10,24]],"date-time":"2025-10-24T15:49:38Z","timestamp":1761320978000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Induced pluripotent stem cells carrying novel APTX mutations presented defective neural differentiation with the accumulation of DNA single-strand breaks"],"prefix":"10.1038","volume":"11","author":[{"given":"Zirui","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yihua","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhirong","family":"Yuan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaibiao","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuqing","family":"Guan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luqin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yawei","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiling","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6162-400X","authenticated-orcid":false,"given":"Yafang","family":"Hu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,10,24]]},"reference":[{"key":"2723_CR1","doi-asserted-by":"publisher","first-page":"189","DOI":"10.1038\/ng1001-189","volume":"29","author":"MC Moreira","year":"2001","unstructured":"Moreira MC, Barbot C, Tachi N, Kozuka N, Uchida E, Gibson T, et al. 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The study was approved by the Ethical Review Committee at Nanfang Hospital, Southern Medical University, Guangzhou, China. The approval number of the ethics committee was no. NFEC-2023-427. All participants provided informed consent. Date of approval: 2023-09-28. For animal experiments, title of the approved project: Study of the molecular mechanisms and therapeutic strategies of\n                      APTX\n                      mutations leading to AOA1 using patient-derived iPSCs. The study was approved by the Ethical Review Committee at the CAS Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health. The approval number of the ethics committee was no. IACUC-2021030. All participants provided informed consent. 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