A homozygous variant in INTS11 links mitosis and neurogenesis defects to a severe neurodevelopmental disorder

• Published in: Cell reports (Cambridge) Vol. 42; no. 12; p. 113445
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 26.12.2023; Elsevier
• Subjects: CP: Neuroscience; CP: Stem cell research; integrator complex; INTS11; mitosis; neurodevelopmental disorder; neurogenesis; INTS11; CP: Stem cell research; neurodevelopmental disorder; CP: Neuroscience; integrator complex; neurogenesis; mitosis
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.113445

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. [Display omitted] •Knockin of an INTS11 endonuclease catalytic mutation into iPSCs slows proliferation•INTS11 catalytic mutation disrupts iPSC mitotic organization, inducing apoptosis•INTS11 dysfunction inhibits neural progenitor cell differentiation•Inefficient INTS11 activity reduces long neural transcripts associated with neurogenesis INTS11 catalytic activity is essential for maintaining efficient gene transcription. Kuang et al. show that an INTS11 catalytic mutation found in two siblings with severe neurodevelopmental disorder affects iPSC mitotic progression, inducing slow proliferation, increased apoptosis, and delayed neural progenitor cell differentiation with preferentially downregulated long transcripts associated with neurogenesis.