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

被引：3

作者：

Kuang, Hanzhe ^{[1
]}

Li, Yunlong ^{[1
]}

Wang, Yixuan ^{[1
]}

Shi, Meizhen ^{[1
,3
]}

Duan, Ranhui ^{[1
]}

Xiao, Qiao ^{[1
]}

She, Haoyuan ^{[1
]}

Liu, Yingdi ^{[1
]}

Liang, Qiaowei ^{[1
,2
]}

Teng, Yanling ^{[1
]}

Zhou, Miaojin ^{[1
]}

Liang, Desheng ^{[1
,2
]}

Li, Zhuo ^{[1
]}

Wu, Lingqian ^{[1
,2
]}

机构：

[1] Cent South Univ, Ctr Med Genet, Sch Life Sci, Hunan Key Lab Med Genet,MOE Key Lab Rare Pediat Di, Changsha 410000, Peoples R China

[2] Hunan Jiahui Genet Hosp, Dept Med Genet, Changsha 410000, Peoples R China

[3] Guangxi Med Univ, Ctr Med Genet & Genom, Affiliated Hosp 2, Nanning, Peoples R China

来源：

CELL REPORTS | 2023年 / 42卷 / 12期

基金：

中国国家自然科学基金; 国家重点研发计划;

关键词：

NEURAL DIFFERENTIATION; DNA-METHYLATION; INTEGRATOR; CDKL5; PROLIFERATION; TRANSCRIPTION; PROTEIN; CPSF-73; GROWTH; GENES;

D O I：

10.1016/j.celrep.2023.113445

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

The INTS11 endonuclease is crucial in modulating gene expression and has only recently been linked to hu-man 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 develop-ment, including the NDD gene CDKL5. The mutant knockin (KI) in induced pluripotent stem cells (iPSCs) dis-turbs 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.

引用

页数：25

共 43 条

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