Disrupting integrator complex subunit INTS6 causes neurodevelopmental disorders and impairs neurogenesis and synapse development

The Integrator complex plays essential roles in RNA polymerase II (RNAPII) transcription termination and RNA processing. Here, we identify INTS6, a subunit of the Integrator complex, as a novel gene associated with neurodevelopmental disorders (NDDs). Through analysis of large NDD cohorts and international collaborations, we identified 23 families harboring monoallelic likely gene-disruptive or de novo missense variants in INTS6. Phenotypic characterization revealed shared features, including language and motor delays, autism, intellectual disability, and sleep disturbances. Using a nervous-system conditional KO (cKO) mouse model, we show that Ints6 deficiency disrupts early neurogenesis, cortical lamination, and synaptic development. Ints6 cKO mice had a thickened ventricular zone/subventricular zone, thinning of the cortical plate, reduced neuronal differentiation, and increased apoptosis in cortical layer 6. Behavioral assessments of heterozygous mice revealed deficits in social novelty preference, spatial memory, and hyperactivity, mirroring phenotypes observed in individuals with INTS6 variants. Molecular analyses further revealed that INTS6 deficiency alters RNAPII dynamics, disrupts transcriptional regulation, and impairs synaptic gene expression. Treatment with a CDK9 inhibitor (CDK9i) reduced RNAPII phosphorylation, thereby limiting its binding to target genes. Notably, CDK9i reversed neurosphere overproliferation and rescued the abnormal dendritic spine phenotype caused by Ints6 deficiency. This work advances understanding of INTS-related NDD pathogenesis and highlights potential therapeutic targets for intervention.

Authors

Institutions

Publication Details

Journal
Journal of Clinical Investigation
Published
2025-09-18
DOI
https://doi.org/10.1172/jci191729
Citations
1
Primary Topic
Genetics and Neurodevelopmental Disorders
Type
article
Field-Weighted Citation Impact
1.82

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Disrupting integrator complex subunit INTS6 causes neurodevelopmental disorders and impairs neurogenesis and synapse development

Xiangbin Jia, Guodong Chen, Katherine H. Kim, Chengxiang Qiu et al.
1 citations
Journal of Clinical Investigation
Genetics and Neurodevelopmental Disorders
1.82
article

Disrupting integrator complex subunit INTS6 causes neurodevelopmental disorders and impairs neurogenesis and synapse development

Xiangbin Jia, Guodong Chen, Katherine H. Kim, Chengxiang Qiu, Haiyan Hou, Xiaoxia Peng, Senwei Tan, Luciana Musante, Andrea Seeley, Ilaria Parenti, Zhengmao Hu, Julián A. Martínez-Agosto, Lior Cohen, Hui Guo, Goran Čuturilo, Erfan Aref‐Eshghi, Jieqiong Tan, Joseph Peeden, Frank J. Kaiser, Jia‐Da Li, Raymond Caylor, Xiaolei Zhang, Alicia Renck, Xinyu Duan, Faxiang Li, Cindy Skinner, Dienke J. Bos, Gaber Bergant, Kristine Bachman, Tobias Bartolomaeus, Rami Abou Jamra, Zhangxue Hu, Sandra Mercier, Conny M.A. van Ravenswaaij‐Arts, Gaël Nicolas, Flavio Faletra, Hanying Wang, Ye Zou, Wenjing Zhao, Kun Xia, Mengyuan Hu, Bertrand Isidor, Benjamin Cogné, Anne-Marie Guerrot, Jingjing Chen, Alma Kuechler, Pan Qian, Borut Peterlin, Zelia Schmederer
article en
1 citations

Abstract

The Integrator complex plays essential roles in RNA polymerase II (RNAPII) transcription termination and RNA processing. Here, we identify INTS6, a subunit of the Integrator complex, as a novel gene associated with neurodevelopmental disorders (NDDs). Through analysis of large NDD cohorts and international collaborations, we identified 23 families harboring monoallelic likely gene-disruptive or de novo missense variants in INTS6. Phenotypic characterization revealed shared features, including language and motor delays, autism, intellectual disability, and sleep disturbances. Using a nervous-system conditional KO (cKO) mouse model, we show that Ints6 deficiency disrupts early neurogenesis, cortical lamination, and synaptic development. Ints6 cKO mice had a thickened ventricular zone/subventricular zone, thinning of the cortical plate, reduced neuronal differentiation, and increased apoptosis in cortical layer 6. Behavioral assessments of heterozygous mice revealed deficits in social novelty preference, spatial memory, and hyperactivity, mirroring phenotypes observed in individuals with INTS6 variants. Molecular analyses further revealed that INTS6 deficiency alters RNAPII dynamics, disrupts transcriptional regulation, and impairs synaptic gene expression. Treatment with a CDK9 inhibitor (CDK9i) reduced RNAPII phosphorylation, thereby limiting its binding to target genes. Notably, CDK9i reversed neurosphere overproliferation and rescued the abnormal dendritic spine phenotype caused by Ints6 deficiency. This work advances understanding of INTS-related NDD pathogenesis and highlights potential therapeutic targets for intervention.

Journal of Clinical InvestigationVol. 135(22)
Kunming University of Science and Technology (CN), GenVec (US), Northwestern University (US), Ben-Gurion University of the Negev (IL), University of Udine (IT), Geisinger Medical Center (US), Centre National de la Recherche Scientifique (FR), University Medical Center Groningen (NL), Central South University (CN), Army Medical University (CN), Inserm (FR), Changsha Medical University (CN), Hunan University (CN), University of Groningen (NL), IRCCS Materno Infantile Burlo Garofolo (IT), Ljubljana University Medical Centre (SI), Barzilai Medical Center (IL), Centre Hospitalier Universitaire de Nantes (FR), University of Belgrade (RS), First People's Hospital of Yunnan Province (CN), Daping Hospital (CN), Center for Human Genetics (US), Normandie Université (FR), Jiangxi Maternal and Child Health Hospital (CN), Driscoll Children's Hospital (US), Medical Genetics Center (DE), ID Genomics (United States) (US), Institute of Human Genetics (PL), Essen University Hospital (DE), Ospedale Santa Maria della Misericordia di Udine (IT), East Tennessee Children's Hospital (US), University Children's Hospital, Belgrade (RS), Institut du Thorax (FR), Greenwood Genetic Center (US), Génétique Médicale & Génomique Fonctionelle (FR), Hunan Provincial Maternal and Child Health Hospital (CN), University of Duisburg-Essen (DE), Université de Rouen Normandie (FR), University of Tennessee at Knoxville (US), University of South China (CN), Leipzig University (DE), Nantes Université (FR)
Simons Foundation Autism Research Initiative, National Natural Science Foundation of China, Central South University, Xiangya Hospital, Central South University, National Key Research and Development Program of China
Openalex Percentile: Top 12%
Genetics and Neurodevelopmental Disorders
1.82
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.