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

作者：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 · 发表于：Cell Reports · 年份：2023 · DOI：10.1016/j.celrep.2023.113445 · 被引用次数：15 · 研究领域：Genetics and Neurodevelopmental Disorders、Chromosomal and Genetic Variations、Epigenetics and DNA Methylation

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.