Recent advances in sequencing analysis of individuals with autism have revealed a large number of genetic variations that are associated with autism. However, the causal role and mechanisms of these mutations are not known.
Compelling evidence suggests that the 15q11-13 chromosomal region is likely to play a role in autism pathogenesis. Mutations of the UBE3A gene, which is located in this region, cause Angelman syndrome (AS), a neurodevelopmental disorder that has strong phenotypic overlap with autism. UBE3A is an E3 ubiquitin ligase and has been shown to be an important regulator of protein homeostasis and synapse development and plasticity. Separately, there is growing evidence that neuronal autophagy plays a role in supporting proper morphological development and synaptic connectivity refinement.
A hallmark symptom of autism spectrum disorders is impairment in social interactions, yet little is known about the neural mechanisms underlying this deficit. In contrast to autism, Williams-Beuren syndrome involves enhanced sociability. The syndrome affects many systems, including the motor, sensory, language, cognitive, emotional and social systems. It is caused by a chromosomal microdeletion. Most individuals with the disorder have relatively preserved language skills in conjunction with high sociability, which are quite opposite from the salient features of autism.
SFARI is pleased to announce that it has awarded 28 grants (15 Pilot Awards and 13 Research Awards) in response to the 2015 Pilot and Research Awards request for applications.
Neuroimaging studies have described altered structural and functional connectivity across brain regions of individuals with autism spectrum disorder (ASD). These findings have led to the hypothesis that altered brain connectivity may provide a key pathophysiological contribution in ASD. However the neurobiological determinants and significance of these findings remain unclear.
On February 6–7, 2020, SFARI convened a two-day workshop to explore the possibility of gene therapies for autism spectrum disorder.
Recent technological advances have identified many ASD risk genes, but how these genes affect brain development and function remains unknown, especially in primates. In the current project, Xinyu Zhao, Qiang Chang, André Sousa and Daifeng Wang plan to genetically manipulate three ASD risk genes in marmoset brain slices followed by multimodal integrative analysis of electrical activities, gene expression and chromatin accessibility of single neurons in the prefrontal cortex. The results will provide new and in-depth knowledge of the neuronal functions of these genes in primate brains.
Thorough understanding the genetic causes of autism spectrum disorder is critical to improving clinical care and advancing biomedical sciences. Yufeng Shen aims to maximize genetic discovery from the exome sequencing data generated by the SPARK project by combining it with machine learning and single cell RNA-seq data analyses.
Michael Halassa, Guoping Feng and colleagues identified a combinatorial strategy to reverse noise hypersensitivity in Ptchd1 knockout mice, while Stephen Scherer, James Ellis and colleagues separately explored the genetic and functional complexity of PTCHD1 in humans.
SFARI is helping to make mouse models of high-risk autism genes and copy number variants available to the research community.
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