Geneticists identify a molecular pathway for autism-related disorders

Geneticists have discovered a molecular trigger for a serious disorder related to autism that has allowed them to begin testing a potential treatment targeting a specific brain protein.

A UT Southwestern study involving humans and mice details one of the rare cases in which researchers have found a specific pathway that causes a neurodevelopmental disorder – in this case a rare disease called Kaufman oculocerebrofacial syndrome (KOS) .

The research gives scientists a better understanding of the potential treatments for KOS, which is characterized by intellectual disability and lack of speech. It also demonstrates the benefits of using modern genetic sequencing to dissect the vast and complex network of mutations at the root of autism spectrum disorder.

"Researchers have already identified broad molecular pathways for different forms of autism spectrum disorders," said Dr. Maria Chahrour, a neurogenetician who led the study published in the Proceedings of the National Academy of Sciences (PNAS). "What we are working on now is the definition of specific pathways like this one that are exploitable and can be targeted for therapies."

Scientists knew that the absence of the UBE3B gene was at the origin of KOS but were unaware of what had happened in the brain and which had caused the symptoms. New PNAS One study showed that KOS could occur when a protein called BCKDK accumulates in the brain in the absence of UBE3B, which would normally regulate the BCKDK protein. Mutations in the BCKDK gene may also cause autism spectrum disorders.

Dr. Chahrour's laboratory found that mice lacking UBE3B and exhibiting BCKDK protein accumulation could no longer vocalize and exhibited other symptoms of the disease, including growth retardation and abnormal brain development. Patients and mice both had characteristic blood abnormalities – a promising development that could eventually lead to a blood test to diagnose the disease.

Meanwhile, Dr. Chahrour's team began testing a therapy to inhibit the accumulation of BCKDK in mice to determine if their brain function and vocalisation are restored. She warns that more research is needed to determine if UBE3B regulates the other pathways contributing to KOS, but she sees this discovery as an important step in understanding the disease.

More generally, the study shows how genetic sequencing can help scientists detect mutations and then test their impact on the brain, which is essential to decipher the biological processes that take place in these conditions and could lead to development of effective treatments.

"Neurodevelopmental disorders, including autism, remain a vast area of ​​unmet need," said Dr. Chahrour. "Although next generation sequencing has changed our field by allowing us to find mutations, our mechanistic understanding of these diseases still presents a huge gap that would allow us to translate preclinical results into successful clinical trials."

Dr. Chahrour leads numerous projects aimed at sequencing the genomes of patients with autism spectrum disorders and other neurodevelopmental disorders to look for mutations causing disease and to study the pathways involved in each of these disorders. # 39; them. Finally, she hopes that these disorders can be diagnosed more accurately and more quickly, not by observable symptoms alone, but by a genetic test.

"Imagine if we could find the precise cause of each of these neurodevelopmental disorders," she said. "We could then start to put them in pathways and find therapies that target the root of the disease, that's what I'm working on."

Provided by
UT Southwestern Medical Center