Haploinsufficiency of the AT-rich interactive domain 1B (ARID1B) gene causes autism spectrum disorder and intellectual disability; however, the neurobiological basis for this is unknown. Here we generated Arid1b-knockout mice and examined heterozygotes to model human patients. Arid1b-heterozygous mice showed a decreased number of cortical GABAergic interneurons and reduced proliferation of interneuron progenitors in the ganglionic eminence. Arid1b haploinsufficiency also led to an imbalance between excitatory and inhibitory synapses in the cerebral cortex. Furthermore, we found that Arid1b haploinsufficiency suppressed histone H3 lysine 9 acetylation (H3K9ac) overall and particularly reduced H3K9ac of the Pvalb promoter, resulting in decreased transcription. Arid1b-heterozygous mice exhibited abnormal cognitive and social behaviors, which were rescued by treatment with a positive allosteric GABA receptor modulator. Our results demonstrate a critical role for Arid1b in interneuron development and behavior and provide insight into the pathogenesis of autism spectrum disorder and intellectual disability.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5726525 | PMC |
| http://dx.doi.org/10.1038/s41593-017-0013-0 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Clonazepam repurposing in patients through conventional RCT and N-of-1 trials: an experimental strategy for orphan disease development.
J Med Genet
December 2024
Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands
Background: Clinical trials for rare disorders have unique challenges due to low prevalence, patient phenotype variability and high expectations. These challenges are highlighted by our study on clonazepam in patients, a common cause of intellectual disability. Previous studies on Arid1b-haploinsufficient mice showed positive effects of clonazepam on various cognitive aspects.
View Article and Find Full Text PDFMicroduplications of ARID1A and ARID1B cause a novel clinical and epigenetic distinct BAFopathy.
Genet Med
January 2025
Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands. Electronic address:
Article Synopsis
- ARID1A and ARID1B duplications are linked to Coffin-Siris syndrome, but ARID1B duplications have not been previously associated with a specific clinical phenotype until now.
- A study analyzed 16 cases of ARID1A and 13 cases of ARID1B duplications, revealing that ARID1A duplications resulted in more severe symptoms, including intellectual disabilities and growth delays, while both groups displayed similar features.
- The research identified unique DNA methylation patterns in ARID1A duplication patients, which differ from those with loss-of-function variants, suggesting the presence of a distinct clinical phenotype for both ARID1A and ARID1B duplications, indicating a new type of
ARID1A-BAF coordinates ZIC2 genomic occupancy for epithelial-to-mesenchymal transition in cranial neural crest specification.
Am J Hum Genet
October 2024
Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, PA, USA; Department of Life Sciences, Imperial College London, London, UK. Electronic address:
Article Synopsis
- The study highlights the role of the BAF chromatin remodeler, specifically the ARID1A subunit, in cranial neural crest cell (CNCC) specification and its link to Coffin-Siris syndrome (CSS).
- ARID1A haploinsufficiency disrupts the epithelial-to-mesenchymal transition (EMT) vital for CNCC migration, while ARID1A-BAF regulates enhancers connected to EMT genes, demonstrating that ZIC2 binding at these enhancers relies on ARID1A.
- The research establishes an important connection between ARID1A and ZIC2 in promoting EMT and successful CNCC delamination, suggesting implications for understanding congenital disorders like CSS.
The missing link: ARID1B non-truncating variants causing Coffin-Siris syndrome due to protein aggregation.
Hum Genet
August 2024
Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, 91054, Erlangen, Germany.
Article Synopsis
- * This study shows that specific non-truncating mutations in ARID1B disrupt protein structure, causing harmful aggregation in cells, while still maintaining protein levels.
- * Findings support the idea that these non-truncating variants could cause disease, encouraging a reevaluation of previously ambiguous variants and enhancing genetic diagnosis for Coffin-Siris syndrome.
Autism spectrum disorder (ASD) presents with diverse cognitive and behavioral abnormalities beginning during early development. Although the neural circuit mechanisms remain unclear, recent work suggests pathology in cortical inhibitory interneurons (INs) plays a crucial role. However, we lack fundamental information regarding changes in the physiology of synapses to and from INs in ASD.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!