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

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

doi:10.1016/j.celrep.2023.113445

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

Cell Rep. 2023 Dec 26;42(12):113445. doi: 10.1016/j.celrep.2023.113445. Epub 2023 Nov 18.

Authors

Hanzhe Kuang¹, Yunlong Li¹, Yixuan Wang¹, Meizhen Shi², Ranhui Duan¹, Qiao Xiao¹, Haoyuan She¹, Yingdi Liu¹, Qiaowei Liang³, Yanling Teng¹, Miaojin Zhou¹, Desheng Liang⁴, Zhuo Li⁵, Lingqian Wu⁶

Affiliations

¹ 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.
² 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, China.
³ 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.
⁴ 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: liangdesheng@sklmg.edu.cn.
⁵ 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.
⁶ 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: wulingqian@sklmg.edu.cn.

PMID: 37980560
DOI: 10.1016/j.celrep.2023.113445

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.

Keywords: CP: Neuroscience; CP: Stem cell research; INTS11; integrator complex; mitosis; neurodevelopmental disorder; neurogenesis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Apoptosis / physiology
Cell Line, Tumor
G2 Phase Cell Cycle Checkpoints
Humans
Induced Pluripotent Stem Cells*
Mitosis / genetics
Neurodevelopmental Disorders* / genetics
Neurogenesis / genetics

Substances

INTS11 protein, human