Autism Mutations Make the Brain Less Flexible

Summary: Study sheds light on how SETD5, a gene associated with ASD, alters behavior and may lead to less flexibility in the brain.

Source: Institute of Science and Technology Austria.

About 1% of patients diagnosed with autism spectrum disorder and intellectual disability have a mutation in a gene called SETD5. Scientists have now discovered what happens on a molecular level when the gene is mutated in mice, and how this changes the mice’s behavior. This is an important step towards understanding how mutations in the SETD5 gene may cause cognitive changes in affected patients. The study was led by Gaia Novarino, Professor at IST Austria, and Kyung-Min Noh, Group leader at the European Molecular Biology Laboratory in Heidelberg, Germany; Elena Deliu, Niccolo Arecco, Jasmin Morandell and Christoph Dotter share first authorship. The results, which suggest that the brains of mice with a SETD5 mutation may be less flexible, are published today in Nature Neuroscience.

In a previous study published in 2014, Gaia Novarino, in collaboration with a group at Bonn University, identified mutations in the gene SETD5 as a relatively frequent cause of intellectual disability and autism. Among patients who are diagnosed with intellectual disability and/or autism spectrum disorder that can be traced to a gene mutation, 1% has a mutation in the gene SETD5. Before the follow-up study published now, however, it was not known what SETD5 does, says Novarino: “This was the motivation for our work. Knowing nothing about this gene, we wanted to find out what its product does.”

The researchers set about characterizing what the SETD5 gene product does on a molecular level and link this to how behavior changes when SETD5 is mutated. This endeavor was not about understanding mouse biology though, Gaia Novarino clarifies. “We want to know what happens in patients who have a mutation in SETD5. To be able to understand this, we made mice that have the same genetic defect as seen in humans.”

For their studies, the researchers characterized what happens in mice which carry one mutated copy of SETD5 and one intact copy of the gene. They found that in the mouse embryo, SETD5 is important for regulating gene transcription, the process by which the blueprint of DNA is turned into a set of instructions for making proteins. In early development, SETD5 plays a role in the specification of tissues, this is the reason why developmental defects are seen when SETD5 is mutated.

Mice help scientists uncover the mechanisms behind autism spectrum disorders and intellectual disability. image is credited to IST Austria/Isabel Chew.

Later on in life, SETD5 regulates gene transcription in dynamic processes when signals are integrated, for example to form memories or during learning. When mice with SETD5 mutation are set a learning challenge, the dynamics of gene transcription is different from that in mice without the mutation.

The researchers hypothesize that mice with a SETD5 mutation have a more inflexible brain. SETD5 mice were found to make memories that are too strong and not easily overwritten. “In the brain, balance and precise response are important. The SETD5 mice make more stable memories, which could make the brain inflexible. Because the brain is less flexible, they cannot easily make new memories or adapt to new situations”, Gaia Novarino explains.

The study authors also found that SETD5 cooperates with other proteins to regulate gene expression during learning and memory formation. Several of these associated genes, when mutated, also lead to intellectual disability and/or autism spectrum disorder in patients, says Kyung-Min Noh. “We have found a cluster of genes that are all related to these disorders.”

Understanding the molecular function of SETD5 and linking it to mouse behavior was an important step towards helping patients. “When we look at the brain of these mice, the structure hasn’t changed. So there is no structural barrier that would give a reason why treating patients with SETD5 mutations wouldn’t be possible”, Novarino explains, “This gives us hope that eventually, we will understand how to treat the cognitive issues of patients with SETD5 mutations. The extent to which the condition is treatable will be seen. We have hope.”

About this neuroscience research article

Source: Elisabeth Guggenberger – Institute of Science and Technology Austria
Publisher: Organized by
Image Source: image is credited to IST Austria/Isabel Chew.
Original Research: Abstract for “Haploinsufficiency of the intellectual disability gene SETD5 disturbs developmental gene expression and cognition” by Elena Deliu, Niccolò Arecco, Jasmin Morandell, Christoph P. Dotter, Ximena Contreras, Charles Girardot, Eva-Lotta Käsper, Alena Kozlova, Kasumi Kishi, Ilaria Chiaradia, Kyung-Min Noh & Gaia Novarino in Nature Neuroscience. Published November 19 2018.

Cite This Article

[cbtabs][cbtab title=”MLA”]Institue of Science and Technology Austria”Autism Mutations Make the Brain Less Flexible.” NeuroscienceNews. NeuroscienceNews, 19 November 2018.
<>.[/cbtab][cbtab title=”APA”]Institue of Science and Technology Austria(2018, November 19). Autism Mutations Make the Brain Less Flexible. NeuroscienceNews. Retrieved November 19, 2018 from[/cbtab][cbtab title=”Chicago”]Institue of Science and Technology Austria”Autism Mutations Make the Brain Less Flexible.” (accessed November 19, 2018).[/cbtab][/cbtabs]


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

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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