A new study shows that mutation in a risk gene for autism interfere with the normal function of the brain’s cerebellum.

Ben and Suli
19 November, 2020

POGZ is an autism spectrum disorder risk gene. How POGZ mutations result in ASD is unclear and animal models are lacking. Here, the authors generate a brain specific Pogz deficient mouse presenting ASD-like behaviour and show the effects of Pogz deficiency in the cerebellum. 

Read More
Around 1% of children are being diagnosed with autism spectrum disorder that involves social, communication, and behavioral challenges. It is still not clear what type of changes in the brain are responsible for the social difficulties.

Now, a new study led by Reut Suliman-Lavie and Ben Title shows that a mutation in a gene implicated in autism has a pronounced effect on brain development and the function of the cerebellum. The researchers mutated the gene specifically in the brain and found that it affects the social and cognitive behavior in mice in a similar way to what was observed in humans with mutations in this gene. They further showed that this gene regulates the activity of many other genes and is important for the proper activity of brain cells in the cerebellum. The finding, reported in Nature Communications, provides a new understanding of how mutations in a single gene lead to autism. While currently there are no effective drugs to treat autism, this discovery could help finding new ways for developing drugs to treat autism by modulating the neural circuits of the cerebellum.

Read the paper published in Nature Communications

Read Less

The most striking feature of psychiatric disorders is the lack of specificity of the genetic risk factors

27 May, 2020

Shahar Shohat, Alana Amelan and Sagiv Shifman review and analyze the functional convergence of genetic risk factors for major neuropsychiatric disorders on molecular pathways, cell types and brain regions during developmental periods.

Read More

"We recently have been tremendously successful in identifying risk genes for psychiatric disorders by applying new technologies and through extensive collaboration between many scientists. In a way, too successful. The prodigious number of candidate risk genes and the genetic overlap between disorders makes the next step of studying the mechanisms challenging. Newly established detailed gene expression databases, covering brain cell types and different developmental stages, together with systems biology approaches, have been used to explore the convergence between genes and divergence between disorders. The results showed that across disorders, risk genes are likely to be intolerant to mutations and preferentially expressed in the brain. The disorders diverge mainly on the relative contribution of rare vs. common variants, and the timing of expression of the risk genes. Thus, the functional enrichment results are still crude and far from illuminating the neurobiological mechanisms for psychiatric disorders. Perhaps the convergence and divergence will only be found at the neural circuit level." 

Read the paper published in Biological Psychiatry

Read Less

Many risk genes for neurodevelopmental disorders are essential in embryonic stem cells

24 October, 2019

Mouse embryonic stem cells (mESCs) are key components in generating mouse models for human diseases and performing basic research on pluripotency, yet the number of genes essential for mESCs is still unknown.

Read More

We performed a genome-wide screen for essential genes in mESCs and compared it to screens in human cells. We found that essential genes are enriched for basic cellular functions, are highly expressed in mESCs, and tend to lack paralog genes. We discovered that genes that are essential specifically in mESCs play a role in pathways associated with their pluripotent state. We show that 29.5% of human genes intolerant to loss-of-function mutations are essential in mouse or human ESCs, and that the human phenotypes most significantly associated with genes essential for ESCs are neurodevelopmental. Our results provide insights into essential genes in the mouse, the pathways which govern pluripotency, and suggest that many genes associated with neurodevelopmental disorders are essential at very early embryonic stages.

Read the paper published in Genome Research


Read Less

How do mutations in the same gene lead to diverse brain disorders

5 April, 2019

Mutations in the AUTS2 gene are found in individuals with variable symptoms and diagnoses including intellectual disability, attention-deficit & hyperactivity disorder or autism. Previous research revealed that the more severe cases tend to have mutations located towards the end of the gene. 

Read More

A new study, led by Dr. Galya Rothkoff and Prof. Sagiv Shifman, has shown that the AUTS2 gene produces two protein forms - a short and a long version, and the precise expression of these protein forms is essential for regulating neurons generation. During differentiation of embryonic stem cells to neurons a shift from the long to the short protein occurs. 

The two forms of protein display different molecular functions, including which proteins they bind, how they regulate the activity of other genes, and how they affect the process of differentiation to neurons. 

The timing of neuron generation is crucial for determining the size of the brain. This study suggests that microcephaly seen in individuals with mutations in AUTS2 may result from faster differentiation of stem cells to neurons. The study shows that mutations affecting the two forms of the protein lead to a more pronounced cell death during differentiation to neurons.  This observation can explain how the location of mutations can affect severity of symptoms, since the two protein forms are affected by mutations in the end of the AUTS2 gene. 

 Read the paper published in Molecular Psychiatry

Read Less