Autism Spectrum Disorder (ASD) affects about 1 in 68 children. Genetics plays a large role in the onset of ASD, but the exact genes involved are not clearly defined. However, a new paper published in Neuron describes how specific genes known to be connected to ASD are active during fetal brain development. Lilia Iakoucheva of the University of California, San Diego headed up the research.
The study focused on copy number variants (CNVs) in particular regions that have previously been connected to ASD. However, the researchers soon learned that not all CNVs were activated during the same growth period. Activation of various CNVs was staggered throughout fetal development.
The two genes, known as KCTD13 and CUL3, have ASD-associated mutations, and become activated around the middle of development. These genes regulate the protein RhoA, which is crucial to brain development. RhoA is responsible for the development and maintenance of neurons, while also assisting in the regulation of their migration.
"The most exciting moment for us was when we realized that the proteins encoded by these genes form a complex that regulates the levels of a third protein, RhoA," Iakoucheva said in a press release. "Suddenly, everything came together and made sense.”
Image credit: UC San Diego School of Medicine
“Our model fits perfectly with what we observe in the patients," co-first author Guan Ning Lin added.
Using zebrafish (a common model organism in genetics), they found that certain mutations on CUL3 adversely affected KCTD13, which, in turn, affected the normal function of RhoA. Just as the zebrafish with these mutations had head sizes that differed from typical development, so do children with ASD. Additionally, the mutations also correlated to the weight of the fish, just as it does in humans.
Moving forward, it is hoped that obtaining a better understanding of these genetic pathways and how they connect to various disorders on the Autism spectrum will allow researhers to manipulate these pathways into a potential treatment.
"The fact that three different types of mutations may act via the same pathway is remarkable," concluded Iakoucheva. "My hope is that we would be able to target it therapeutically. If we can discover the precise mechanism and develop targeted treatments for a handful of children, or even for a single child with autism, I would be happy.”