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


Author(s): Deliu, Elena; Arecco, Niccoló; Morandell, Jasmin; Dotter, Christoph; Contreras, Ximena; Girardot, Charles; Käsper, Eva L; Kozlova, Alena; Kishi, Kasumi; Chiaradia, Ilaria; Noh, Kyung M; Novarino, Gaia
Article Title: Haploinsufficiency of the intellectual disability gene SETD5 disturbs developmental gene expression and cognition
Affiliation IST Austria
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.
Journal Title: Nature Neuroscience
Volume: 21
Issue 12
ISSN: 1546-1726
Publisher: Nature Publishing Group  
Date Published: 2018-11-19
Start Page: 1717
End Page: 1727
Sponsor: This work was supported by the Simons Foundation Autism Research Initiative (grant 401299) to G.N. and the DFG (SPP1738 grant NO 1249) to K.-M.N.
DOI: 10.1038/s41593-018-0266-2
Open access: no