Haploinsufficiency of the intellectual disability gene SETD5 disturbs developmental gene expression and cognition

Deliu, Elena and Arecco, Niccolò and Morandell, Jasmin and Dotter, Christoph P and Contreras, Ximena and Girardot, Charles and Käsper, Eva-Lotta and Kozlova, Alena and Kishi, Kasumi and Chiaradia, Ilaria and Noh, Kyung-Min and Novarino, Gaia (2018) Haploinsufficiency of the intellectual disability gene SETD5 disturbs developmental gene expression and cognition. Nature Neuroscience, 21 (12). pp. 1717-1727. ISSN 1546-1726 (Submitted)

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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.

Item Type: Article
DOI: 10.1038/s41593-018-0266-2
Subjects: 500 Science > 570 Life sciences; biology
Research Group: Novarino Group
Depositing User: Doris Ernst
Date Deposited: 06 Dec 2018 14:17
Last Modified: 06 Dec 2018 14:17
URI: https://repository.ist.ac.at/id/eprint/1071

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