Haploinsufficiency of the intellectual disability gene SETD5 disturbs developmental gene expression and cognition
Abstract
SETD5 gene mutations have been identified as a frequent cause of idiopathic intellectual disability. Here we show that Setd5-haploinsufficient mice present developmental defects such as abnormal brain-to-body weight ratios and neural crest defect-associated phenotypes. Furthermore, Setd5-mutant mice show impairments in cognitive tasks, enhanced long-term potentiation, delayed ontogenetic profile of ultrasonic vocalization, and behavioral inflexibility. Behavioral issues are accompanied by abnormal expression of postsynaptic density proteins previously associated with cognition. Our data additionally indicate that Setd5 regulates RNA polymerase II dynamics and gene transcription via its interaction with the Hdac3 and Paf1 complexes, findings potentially explaining the gene expression defects observed in Setd5-haploinsufficient mice. Our results emphasize the decisive role of Setd5 in a biological pathway found to be disrupted in humans with intellectual disability and autism spectrum disorder.
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Loss of SETD5 results in activation of neuronal genes and Wnt signaling in mouse fetal tissue and human cells.
“Recent studies of SETD5 in mouse fetal tissue and human cells have reported that loss of SETD5 results in the activation of neuronal genes and Wnt signaling (Deliu et al., 2018).”
From Getting to the cores of autism (2019) · cites this paper as Deliu et al., 2018
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- Authors
- Deliu, E., Arecco, N., Morandell, J., Dotter, C. P., Contreras, X., Girardot, C., Käsper, E.-L., Kozlova, A., Kishi, K., Chiaradia, I., Noh, K.-M., & Novarino, G.
- Affiliations
- Institute of Science and Technology Austria (AT)
- Heidelberg University (DE)
- European Molecular Biology Laboratory (DE)
- Corresponding author
- Noh, Kyung-Min
- Novarino, Gaia
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2018-11-19
- Volume
- 21
- Issue
- 12
- Pages
- 1717-1727
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- OpenAlex
- W2900030163
- Cited by
- 89
- References
- 85
- Citations by year
- 2026: 9 · 2025: 6 · 2024: 16 · 2023: 14 · 2022: 14 · 2021: 12 · 2020: 10 · 2019: 7 · 2018: 1
- FWCI
- 4.59
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- SETD5, haploinsufficiency, intellectual disability, autism spectrum disorder, brain-to-body weight ratio, neural crest defects, long-term potentiation, ultrasonic vocalizations, behavioral inflexibility, postsynaptic density proteins, gene transcription, HDAC3, Paf1 complex, developmental gene expression, cognition
- MeSH terms
- Animals, Behavior, Animal, Brain, Cognition, Methyltransferases, RNA Polymerase II, Vocalization, Animal, Gene Expression, Long-Term Potentiation, Mice, Knockout, Gene Expression Regulation, Developmental, Haploinsufficiency
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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