Summary: For years, the “gender bias” in autism—where males are diagnosed 3–4 times more often than females—has been a biological enigma. A breakthrough study finally provides an answer. Researchers discovered that mutations in the MDGA1 gene break the balance of brain circuits, leading to autism-like traits in males.
However, females are protected by their estrogen-signaling system, which acts as a “neural shield.” By leveraging this discovery, the team successfully used an FDA-approved estrogen modulator, bazedoxifene, to reverse autism symptoms in male models.
Key Facts
- The MDGA1 Discovery: This is the first study to identify the MDGA1 missense mutation as a direct cause of autism symptoms. The MDGA1 protein normally prevents brain circuits from becoming “over-excited.”
- Gender Bias Explained: In MDGA1-mutated models, males showed severe impairment in social communication. Females, however, maintained normal behavior because estrogen protected their neural circuits from the mutation’s damage.
- Synaptic Breakdown: The mutation causes a drop in the phosphorylation of Synapsin II, a protein essential for transmitting signals between nerve cells. This drop destabilizes the entire brain network.
- Drug Repurposing: The researchers administered bazedoxifene (an FDA-approved drug for osteoporosis/menopause) to male mice. It restored Synapsin II function and normalized autism-like behaviors, such as abnormal vocalization.
Source: DGIST
The Center for Synapse Diversity and Specificity (Director: Professor Jaewon Ko), Department of Neuroscience, Daegu Gyeongbuk Institute of Science & Technology (DGIST; President Kunwoo Lee), has discovered that a mutation of the MDGA1 gene, a key factor modulating the connections and characteristics between nerve cells, serves as a new cause of autism spectrum disorder (ASD), and suggested the possibility of a drug to treat the disorder.
This study holds great significance, as it provides biological clues on why autism is more frequent among men than among women.
ASD is a neurodevelopmental disorder. Characteristic traits include a lack of social interactions and repetitive behaviors. While the incidence and diagnosis rates of ASD are generally known to be about three to four times higher among men than among women, the clear biological cause of this gender bias has remained a mystery.
This study has solved the mystery and provided molecular biological clues on why autism occurs more frequently among men.
With this joint study by an international research team from Spain, the research group discovered the MDGA1 missense mutation in patients with autism symptoms: a world first. According to the study’s findings, the MDGA1 protein acts as a modulator that inhibits brain neural circuits from becoming over-excited.
The study, however, found that if this gene is mutated, the function (phosphorylation level) of the protein (Synapsin II), which helps to transmit signals between nerve cells, drops and subsequently breaks the balance of brain neural circuits.
Interestingly, the failure of these brain circuits manifests differently between males and females. In the MDGA1-mutated mouse model developed by the research group, male mice showed clear autism-like behaviors, such as impaired social communication skills, while female mice maintained normal behavioral patterns.
The research group attributed this effect to the estrogen-signaling system in females that protects against abnormalities in neural circuits caused by gene deletions.
On the basis of this defense mechanism, the research group administered bazedoxifene, a selective estrogen receptor modulator already approved by the US Food and Drug Administration (FDA), to mutated male mice.
The research group confirmed that this restored the function of the impaired neuroprotein (Synapsin II phosphorylation) and returned autism-like behaviors, such as abnormal ultrasonic vocalization and startle responses, to normal levels.
“This study holds huge significance as not only did it identify new genetic factors of ASD, whose exact cause was difficult to determine, but it also identified the molecular mechanism by which gender differences occur,” said Professor Jaewon Ko.
“More specifically, we will continue follow-up research for future clinical applications, as it opens up the possibility that bazedoxifene, a drug whose safety is already proven, can be used as a new treatment option for autism.”
Meanwhile, regarding this outcome of the study, former Postdoctoral Researcher Seungjun Kim (currently: Postdoctoral Researcher at Rutgers University, USA) and Postdoctoral Researcher Hyunho Kim at the Center for Synapse Diversity and Specificity (Director: Professor Jaewon Ko), Department of Neuroscience, DGIST, participated as co-first authors. In addition, not only the research team by Dr. Alberto Fernández-Jaén at Hospital Universitario Quironsalud, Spain, but also Professor Jiwon Um and Professor Wookyung Yu at DGIST, Dr. Jinyoung Kim at the Korea Basic Science Institute, Dr. Seokkyu Kwon at the Korea Institute of Science and Technology, Professor Junyong Ahn at Korea University, Professor Homin Kim at KAIST from Korea, and Professor Wonchan Oh at the University of Colorado, USA, participated in this study.
The results of this study were published online on March 20, 2026, in EMBO Molecular Medicine, one of the top international journals in the field.
Funding: This study was funded by the Leader Research Program, the Mid-Career Researcher Support Program, and Sejong Science Fellowship by the Ministry of Science and ICT and the National Research Foundation of Korea.
Key Questions Answered:
A: It’s called the “Female Protective Effect.” Female brains naturally have higher levels of estrogen signaling, which acts like a backup generator for the brain’s circuits. When the MDGA1 mutation “shuts off the lights,” estrogen provides enough power to keep the system running normally. Males lack this high-level “backup,” so the circuit failure is immediate and visible.
A: It’s a potential treatment, not necessarily a cure. The drug restored a specific protein function (Synapsin II) that was broken by the MDGA1 mutation. Because bazedoxifene is already FDA-approved and proven safe for other uses, it could move to clinical trials for autism much faster than a brand-new drug.
A: No. Autism is genetically diverse (heterogeneous). This specific mutation is one of many causes, but it is a “first-in-world” discovery that helps explain the broader biological reason why so many more men are affected by the disorder across the board.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- Journal paper reviewed in full.
- Additional context added by our staff.
About this autism research news
Author: Wankyu Lim
Source: DGIST
Contact: Wankyu Lim – DGIST
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Bazedoxifene reverses sexually dimorphic autistic-like abnormalities in biallelic MDGA1-mutant mice” by Seungjoon Kim, Hyeonho Kim, Javier Porta Pelayo, Sara Alvarez, Gyubin Jang, Jinhu Kim, Byeongchan Kim, Victoria M Hoelscher, Beatriz Calleja-Pérez, Hyunsu Jung, Yeji Yang, Hea Ji Lee, Jihae Lee, Seoyeon Kim, Mar Jiménez de la Peña, Yelin Lee, Sohye Kim, Ah-reum Han, Dong Sun Lee, Sangho Ji, Wookyung Yu, Ho Min Kim, Joon-Yong An, Won Chan Oh, Seok-Kyu Kwon, Jin Young Kim, Ji Won Um, Alberto Fernández-Jaén & Jaewon Ko. EMBO Molecular Medicine
DOI:10.1038/s44321-026-00402-y
Abstract
Bazedoxifene reverses sexually dimorphic autistic-like abnormalities in biallelic MDGA1-mutant mice
MDGA1 reportedly suppresses GABAergic synaptic inhibition and may be associated with schizophrenia. However, it has been unclear whether and how MDGA1 dysfunction causes neurodevelopmental disorders.
Here, we describe two patients with autism spectrum disorder (ASD) carrying missense mutations in MDGA1: p.Val116Met/p.Ala688Val and p.Tyr635Cys/p.Glu756Gln. Murine in utero overexpression of MDGA1 p.Val116Met/p.Ala688Val alters normal cortical neuron migration and impairs ultrasonic vocalizations (USVs).
The p.Tyr635Cys/p.Glu756Gln substitution disrupts the triangular extracellular structure of MDGA1 and renders it unable to impact GABAergic synapses in hippocampal CA1 neurons.
Male Mdga1 knock-in (KI) mouse pups and adults harboring the p.Tyr636Cys/p.Glu751Gln mutation exhibit impaired USVs and sensorimotor gating, similar to male Mdga1 conditional knockout (cKO) mice.
No behavioral deficits were seen in female counterparts. Bazedoxifene (a selective estrogen receptor modulator) treatment of male Mdga1Y636C/E751Q KI mice rescues the changes in the expression and phosphorylation of a subset of GABAergic synaptic proteins, as well as behavioral performance and GABAergic synaptic strength.
Thus, different MDGA1 mutations manifest as distinct MDGA1 dysfunctions and are likely to cause ASD via sexually dimorphic loss-of-function and/or gain-of-function mechanisms.
