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A homozygous variant in INTS11 links mitosis and neurogenesis defects to a severe neurodevelopmental disorder.
Kuang, Hanzhe; Li, Yunlong; Wang, Yixuan; Shi, Meizhen; Duan, Ranhui; Xiao, Qiao; She, Haoyuan; Liu, Yingdi; Liang, Qiaowei; Teng, Yanling; Zhou, Miaojin; Liang, Desheng; Li, Zhuo; Wu, Lingqian.
Afiliação
  • Kuang H; Center 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.
  • Li Y; Center 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.
  • Wang Y; Center 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.
  • Shi M; Center 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, C
  • Duan R; Center 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.
  • Xiao Q; Center 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.
  • She H; Center 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.
  • Liu Y; Center 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.
  • Liang Q; Center 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.
  • Teng Y; Center 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.
  • Zhou M; Center 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.
  • Liang D; Center 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. Electronic address: liangd
  • Li Z; Center 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. Electronic address: lizhuo@sklmg.edu.cn.
  • Wu L; Center 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. Electronic address: wuling
Cell Rep ; 42(12): 113445, 2023 12 26.
Article em En | MEDLINE | ID: mdl-37980560
ABSTRACT
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.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Células-Tronco Pluripotentes Induzidas / Transtornos do Neurodesenvolvimento Idioma: En Ano de publicação: 2023 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Células-Tronco Pluripotentes Induzidas / Transtornos do Neurodesenvolvimento Idioma: En Ano de publicação: 2023 Tipo de documento: Article