"Why Is Autism More Common in Males?"... DGIST Identifies Genetic Cause of Sex Differences in Autism [Reading Science]

Molecular Mechanism Behind Male-Biased Autism Uncovered
Potential for Repurposing FDA-Approved Drug Suggested

A Korean research team has identified a genetic cause that may explain why autism spectrum disorder is more prevalent in males. By successfully repairing disrupted brain circuits using a drug that regulates female hormones, the team has also suggested the possibility of new therapeutic strategies.

On April 1, DGIST (Daegu Gyeongbuk Institute of Science and Technology) announced that Professor Jaewon Ko's team from the Laboratory of Brain Science and Synaptic Diversity and Specificity has confirmed that variation in the MDGA1 gene, which regulates connections between neurons, is a novel cause of autism spectrum disorder. This discovery is particularly significant as it provides molecular biological clues to why autism is three to four times more common in males than in females.

Schematic diagram of the mechanism of gender differences in autism onset and drug (bazedoxifene) treatment process. In the MDGA1 complex mutant mouse model, females matured into adults with normalized synaptic function, whereas males exhibited persistent autism-like behaviors. After bazedoxifene administration, synaptic abnormalities and communication deficits in males improved. Provided by the research team

Autism spectrum disorder is a representative neurodevelopmental condition characterized by impaired social interaction and repetitive behaviors. While the male-biased prevalence has been well documented, biological explanations for this difference have remained insufficient.

The research team, in collaboration with Spanish researchers, became the first in the world to identify a missense mutation in the MDGA1 gene in patients with autism. MDGA1 plays a role in maintaining balance in neural circuits to prevent excessive excitation in the brain. However, when a mutation occurs, the phosphorylation function of synapsin II is compromised, disrupting neural circuit balance and resulting in autism-related symptoms.

Females Remain Unaffected While Only Males Show Abnormalities... Estrogen Protects Brain Circuits

The central finding of this study is the difference according to sex. In the mutant mouse model developed by the team, males exhibited pronounced autism-like behaviors such as impaired social communication, while females maintained normal behaviors. The team interpreted this as a result of the estrogen signaling system in females defending against circuit damage caused by genetic abnormalities.

The team also confirmed the therapeutic potential. They administered Bazedoxifene, a selective estrogen receptor modulator approved by the U.S. Food and Drug Administration (FDA), to male mutant mice. As a result, the impaired function of synapsin II was restored, and autism-like behaviors such as abnormal ultrasonic vocalizations and exaggerated startle responses were normalized.

Research team photo. From the left: Professor Jaewon Ko of DGIST, Postdoctoral Researcher Seungjun Kim of Rutgers University, USA, Postdoctoral Researcher Hyeonho Kim of DGIST. Courtesy of DGIST

Professor Jaewon Ko said, "This study is meaningful in that it simultaneously identified a new genetic factor for autism spectrum disorder and the molecular mechanism underlying sex differences. Since we have confirmed the potential for drug repurposing with a medication whose safety has already been established, we plan to continue follow-up research for clinical application."

This achievement is distinguished by being the first to demonstrate the role of MDGA1, an inhibitory synapse regulatory factor, in human genomes and animal models, whereas previous autism research has mainly focused on excitatory synapse abnormalities. There is potential for this to lead to early diagnostic biomarkers for patients with MDGA1 mutations, as well as therapeutic strategies based on drug repurposing.

The research findings were published in the online edition of the international journal 'EMBO Molecular Medicine' on March 20.

This content was produced with the assistance of AI translation services.