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

Area of Science:

• Genetics and Molecular Biology
• Neuroscience
• Developmental Biology

Background:

• The Integrator complex is crucial for RNA polymerase II (RNAPII) transcription termination and RNA processing.
• Neurodevelopmental disorders (NDDs) encompass a range of conditions affecting brain development.

Purpose of the Study:

• To identify novel genes associated with NDDs.
• To investigate the role of INTS6 in neurodevelopment and NDD pathogenesis.

Main Methods:

• Analysis of large NDD cohorts and international collaborations to identify INTS6 variants.
• Phenotypic characterization of affected individuals and a nervous-system conditional knockout (cKO) mouse model.
• Molecular analyses of RNAPII dynamics, transcriptional regulation, and synaptic gene expression.
• In vivo testing of a CDK9 inhibitor (CDK9i) for therapeutic potential.

Main Results:

• Identified 23 families with monoallelic INTS6 variants associated with NDDs.
• INTS6 deficiency in mice disrupted neurogenesis, cortical lamination, and synaptic development, leading to behavioral deficits.
• Molecular analyses revealed altered RNAPII dynamics and impaired synaptic gene expression in Ints6-deficient models.
• CDK9i treatment reversed neurosphere overproliferation and rescued abnormal dendritic spine phenotypes.

Conclusions:

• INTS6 is a novel gene associated with NDDs, with variants causing significant neurodevelopmental and cognitive impairments.
• INTS6 deficiency disrupts fundamental processes of neurodevelopment, including neurogenesis and synaptic function.
• Targeting CDK9 offers a potential therapeutic strategy for INTS-related NDDs.