Jason Yi finds the important role that the molecule pictured above, UBE3A, has in the development of autism spectrum disorder. (Source: Wikimedia Commons)
On Monday, January 11, 2016, faculty candidate Jason Yi, Ph.D., presented his findings, published in Cell, on a molecular basis for autism (1, 2).
Autism spectrum disorder (ASD) is a developmental disorder associated with an impaired ability to process social stimuli. ASD has attracted more attention in recent years as it has become increasingly common. However, until now, the scientific community had not identified a molecular basis for the disorder.
Previous studies had found an association between ASD and the overexpression of protein ligase UBE3A, but the scientific community did not know what caused the overexpression. The vast array of genetic mutations in individuals with ASD made it difficult to determine which mutations, or combinations of mutations, caused the overexpression of UBE3A and ASD.
Yi and his team sought to find whether the overexpression was caused by a genetic toggle switch. The team searched for mutations that change UBE3A expression, speculating that failure to phosphorylate the UBE3A gene may cause autism. They used CRISPR-Cas9 technology to test their hypothesis, inducing phosphorylation of UBE3A in fetal mice. Additionally, they mutated the gene in a different set of mice to prevent phosphorylation of UBE3A. They then assessed the mice after birth and measured their expression of UBE3A.
The team found that the mutant gene they targeted served as the genetic toggle switch for UBE3A expression. Preventing the phosphorylation of UBE3A essentially caused the toggle switch to break, leaving it in the on position and causing overexpression of UBE3A and autism to develop in the mice. While Yi was working on publishing his findings, several individuals questioned whether this mechanism is applicable to humans, however, studies later found the same phosphorylation-preventing mutation in autistic children.
This discovery provides a molecular explanation for the overexpression of UBE3A, which has puzzled the scientific community for years. In the future, Yi hopes to find a developmental model for ASD, and scientists will continue to search for other molecular bases of autism.
References:
- Yi, J. J. (2015). An Autism-Linked Mutation Disables Phosphorylation Control of UBE3A. Cell, 162(4), 795-807. doi: 10.1016/j.cell.2015.06.045
- Yi, J. (2016). Tracing a Molecular Pathway to Autism. Personal Collection of Jason Yi, University of North Carolina, Chapel Hill, North Carolina.