A homozygous variant in INTS11 links mitosis and neurogenesis defects to a severe neurodevelopmental disorder
Summary: The INTS11 endonuclease is crucial in modulating gene expression and has only recently been linked to human neurodevelopmental disorders (NDDs). However, how INTS11 participates in human development and disease remains unclear. Here, we identify a homozygous INTS11 variant in two siblings w...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-12-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124723014572 |
| _version_ | 1827714777072271360 |
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| author | Hanzhe Kuang Yunlong Li Yixuan Wang Meizhen Shi Ranhui Duan Qiao Xiao Haoyuan She Yingdi Liu Qiaowei Liang Yanling Teng Miaojin Zhou Desheng Liang Zhuo Li Lingqian Wu |
| author_facet | Hanzhe Kuang Yunlong Li Yixuan Wang Meizhen Shi Ranhui Duan Qiao Xiao Haoyuan She Yingdi Liu Qiaowei Liang Yanling Teng Miaojin Zhou Desheng Liang Zhuo Li Lingqian Wu |
| author_sort | Hanzhe Kuang |
| collection | DOAJ |
| description | Summary: The INTS11 endonuclease is crucial in modulating gene expression and has only recently been linked to human neurodevelopmental disorders (NDDs). However, how INTS11 participates in human development and disease remains unclear. Here, we identify a homozygous INTS11 variant in two siblings with a severe NDD. The variant impairs INTS11 catalytic activity, supported by its substrate’s accumulation, and causes G2/M arrest in patient cells with length-dependent dysregulation of genes involved in mitosis and neural development, including the NDD gene CDKL5. The mutant knockin (KI) in induced pluripotent stem cells (iPSCs) disturbs their mitotic spindle organization and thus leads to slow proliferation and increased apoptosis, possibly through the decreased neurally functional CDKL5-induced extracellular signal-regulated kinase (ERK) pathway inhibition. The generation of neural progenitor cells (NPCs) from the mutant iPSCs is also delayed, with long transcript loss concerning neurogenesis. Our work reveals a mechanism underlying INTS11 dysfunction-caused human NDD and provides an iPSC model for this disease. |
| first_indexed | 2024-03-10T19:05:15Z |
| format | Article |
| id | doaj.art-99137d83bbf747d8a0d8c85994c6ba90 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-03-10T19:05:15Z |
| publishDate | 2023-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-99137d83bbf747d8a0d8c85994c6ba902023-11-20T04:11:42ZengElsevierCell Reports2211-12472023-12-014212113445A homozygous variant in INTS11 links mitosis and neurogenesis defects to a severe neurodevelopmental disorderHanzhe Kuang0Yunlong Li1Yixuan Wang2Meizhen Shi3Ranhui Duan4Qiao Xiao5Haoyuan She6Yingdi Liu7Qiaowei Liang8Yanling Teng9Miaojin Zhou10Desheng Liang11Zhuo Li12Lingqian Wu13Center for Medical Genetics, Hunan Key Laboratory of Medical Genetics, MOE Key Lab of Rare Pediatric Diseases, School of Life Sciences, Central South University, Changsha 410000, ChinaCenter for Medical Genetics, Hunan Key Laboratory of Medical Genetics, MOE Key Lab of Rare Pediatric Diseases, School of Life Sciences, Central South University, Changsha 410000, ChinaCenter for Medical Genetics, Hunan Key Laboratory of Medical Genetics, MOE Key Lab of Rare Pediatric Diseases, School of Life Sciences, Central South University, Changsha 410000, ChinaCenter for Medical Genetics, Hunan Key Laboratory of Medical Genetics, MOE Key Lab of Rare Pediatric Diseases, School of Life Sciences, Central South University, Changsha 410000, China; Center for Medical Genetics and Genomics, The Second Affiliated Hospital of Guangxi Medical University, Nanning, ChinaCenter for Medical Genetics, Hunan Key Laboratory of Medical Genetics, MOE Key Lab of Rare Pediatric Diseases, School of Life Sciences, Central South University, Changsha 410000, ChinaCenter for Medical Genetics, Hunan Key Laboratory of Medical Genetics, MOE Key Lab of Rare Pediatric Diseases, School of Life Sciences, Central South University, Changsha 410000, ChinaCenter for Medical Genetics, Hunan Key Laboratory of Medical Genetics, MOE Key Lab of Rare Pediatric Diseases, School of Life Sciences, Central South University, Changsha 410000, ChinaCenter for Medical Genetics, Hunan Key Laboratory of Medical Genetics, MOE Key Lab of Rare Pediatric Diseases, School of Life Sciences, Central South University, Changsha 410000, ChinaCenter for Medical Genetics, Hunan Key Laboratory of Medical Genetics, MOE Key Lab of Rare Pediatric Diseases, School of Life Sciences, Central South University, Changsha 410000, China; Department of Medical Genetics, Hunan Jiahui Genetics Hospital, Changsha 410000, ChinaCenter for Medical Genetics, Hunan Key Laboratory of Medical Genetics, MOE Key Lab of Rare Pediatric Diseases, School of Life Sciences, Central South University, Changsha 410000, ChinaCenter for Medical Genetics, Hunan Key Laboratory of Medical Genetics, MOE Key Lab of Rare Pediatric Diseases, School of Life Sciences, Central South University, Changsha 410000, ChinaCenter for Medical Genetics, Hunan Key Laboratory of Medical Genetics, MOE Key Lab of Rare Pediatric Diseases, School of Life Sciences, Central South University, Changsha 410000, China; Department of Medical Genetics, Hunan Jiahui Genetics Hospital, Changsha 410000, China; Corresponding authorCenter for Medical Genetics, Hunan Key Laboratory of Medical Genetics, MOE Key Lab of Rare Pediatric Diseases, School of Life Sciences, Central South University, Changsha 410000, China; Corresponding authorCenter for Medical Genetics, Hunan Key Laboratory of Medical Genetics, MOE Key Lab of Rare Pediatric Diseases, School of Life Sciences, Central South University, Changsha 410000, China; Department of Medical Genetics, Hunan Jiahui Genetics Hospital, Changsha 410000, China; Corresponding authorSummary: The INTS11 endonuclease is crucial in modulating gene expression and has only recently been linked to human neurodevelopmental disorders (NDDs). However, how INTS11 participates in human development and disease remains unclear. Here, we identify a homozygous INTS11 variant in two siblings with a severe NDD. The variant impairs INTS11 catalytic activity, supported by its substrate’s accumulation, and causes G2/M arrest in patient cells with length-dependent dysregulation of genes involved in mitosis and neural development, including the NDD gene CDKL5. The mutant knockin (KI) in induced pluripotent stem cells (iPSCs) disturbs their mitotic spindle organization and thus leads to slow proliferation and increased apoptosis, possibly through the decreased neurally functional CDKL5-induced extracellular signal-regulated kinase (ERK) pathway inhibition. The generation of neural progenitor cells (NPCs) from the mutant iPSCs is also delayed, with long transcript loss concerning neurogenesis. Our work reveals a mechanism underlying INTS11 dysfunction-caused human NDD and provides an iPSC model for this disease.http://www.sciencedirect.com/science/article/pii/S2211124723014572CP: NeuroscienceCP: Stem cell research |
| spellingShingle | Hanzhe Kuang Yunlong Li Yixuan Wang Meizhen Shi Ranhui Duan Qiao Xiao Haoyuan She Yingdi Liu Qiaowei Liang Yanling Teng Miaojin Zhou Desheng Liang Zhuo Li Lingqian Wu A homozygous variant in INTS11 links mitosis and neurogenesis defects to a severe neurodevelopmental disorder Cell Reports CP: Neuroscience CP: Stem cell research |
| title | A homozygous variant in INTS11 links mitosis and neurogenesis defects to a severe neurodevelopmental disorder |
| title_full | A homozygous variant in INTS11 links mitosis and neurogenesis defects to a severe neurodevelopmental disorder |
| title_fullStr | A homozygous variant in INTS11 links mitosis and neurogenesis defects to a severe neurodevelopmental disorder |
| title_full_unstemmed | A homozygous variant in INTS11 links mitosis and neurogenesis defects to a severe neurodevelopmental disorder |
| title_short | A homozygous variant in INTS11 links mitosis and neurogenesis defects to a severe neurodevelopmental disorder |
| title_sort | homozygous variant in ints11 links mitosis and neurogenesis defects to a severe neurodevelopmental disorder |
| topic | CP: Neuroscience CP: Stem cell research |
| url | http://www.sciencedirect.com/science/article/pii/S2211124723014572 |
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