Researchers at the UC-San Diego School of Medicine have done a study that has linked autism-related mutations to a pathway that regulates brain development. They have shown how specific genes which are connected to Autism are active during fetal brain development. These findings were published in the February 18th issue of the journal Neuron.
Autistic disorder (or Autism) is the most common condition amongst a group of developmental disorders called Autism spectrum disorders (ASDs). People with autism have difficulties in social interaction, display repetitive or obsessive behavior and have problems with verbal and non-verbal communication. With early diagnosis, sustained therapy and medication, substantial improvement can be achieved and can help the person lead a near-normal life. Autism has a genetic basis too, though the genes which are involved in it, is not yet clearly defined.
These researchers studied a set of well-known autism-related mutations called copy number variants (CNVs) which arise due to spontaneous deletions or duplications in genetic material during meiosis. “One surprising thing that we immediately observed was that different CNVs seemed to be turned on in different developmental periods,” said Iakoucheva, the lead author.
They noted one particular CNV located in a region of the genome known as 16p11.2, which contained genes that were active during the late mid-fetal period. Ultimately, they identified a network of genes that showed a similar pattern of activation including KCTD13 within 16p11.2 and CUL3, a gene from a different chromosome that is mutated in children with autism.
“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,” said Iakoucheva.
Finally, they confirmed that nonsense mutations in CUL3, a gene which is identified in ASD patients, disrupts the physical interaction between CUL3 and KCTD13 genes, which in turn may impact RhoA levels and dysregulate the RhoA pathway. Rho proteins play critical roles in migration of neurons and brain morphogenesis at early stages of brain development. The levels of RhoA protein influences head and body size in zebrafish, a model organism which is used by geneticists to study gene functions. Children with 16p11.2 CNV also have enlarged or decreased head sizes and suffer from obesity or are underweight.
“Suddenly, everything came together and made sense.”
“Our model fits perfectly with what we observe in the patients,” said Guan Ning Lin, PhD, a fellow in Iakoucheva’s laboratory and co-first author with Roser Corominas, PhD.
Interestingly, the RhoA pathway has recently been implicated in a rare form of autism called Timothy syndrome, which is caused by the mutation in a completely different gene. “The fact that three different types of mutations may act via the same pathway is remarkable,” said Iakoucheva. “My hope is that we would be able to target it therapeutically.”
Iakoucheva and her colleagues are planning to test RhoA pathway inhibitors using a stem cell model of autism. “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,” she said.
The original publication can be accessed here.