Summary: For years, researchers have puzzled over why autism is diagnosed three to four times more often in males than in females. A new study now provides a molecular explanation: mutations in the MDGA1 gene disrupt the balance of brain circuits and produce autism-like traits in males. Female brains are protected by estrogen signaling, which acts as a neural safeguard. Using this insight, the team repurposed an FDA-approved selective estrogen receptor modulator, bazedoxifene, and reversed autism-like symptoms in male mouse models.
This discovery clarifies a long-standing biological mystery about sex differences in autism and points toward a promising therapeutic direction.
Key Facts
- MDGA1 mutation identified: The study is the first to link specific MDGA1 missense mutations directly to autism-like behaviors. Normally, MDGA1 helps prevent excessive excitation in neural circuits.
- Sex difference explained: Male MDGA1-mutant mice showed marked social and communication impairments, while females retained typical behavior because estrogen signaling provided protection for neural circuits.
- Synaptic instability: The MDGA1 mutation reduces phosphorylation of Synapsin II, a protein crucial for neurotransmitter release. This change destabilizes GABAergic synapses and alters network balance.
- Drug repurposing: Treating male mutant mice with bazedoxifene, an FDA-approved estrogen receptor modulator, restored Synapsin II phosphorylation and normalized behaviors such as ultrasonic vocalizations and startle responses.
Source: DGIST
The Center for Synapse Diversity and Specificity (Director: Professor Jaewon Ko), Department of Neuroscience, Daegu Gyeongbuk Institute of Science & Technology (DGIST), reports that mutations in the MDGA1 gene can cause autism spectrum disorder (ASD) by altering connections and signaling among neurons. The group also demonstrates a pharmacological strategy to counteract these effects.
Autism spectrum disorder is a neurodevelopmental condition characterized by difficulties in social interaction and repetitive behaviors. Although ASD is diagnosed more frequently in males—typically three to four times more often—the biological basis for this sex bias has been unclear. This study presents molecular evidence that helps explain why males are more vulnerable in some genetic contexts.
In collaboration with international partners from Spain, the team identified novel MDGA1 missense mutations in people with ASD. MDGA1 normally acts as a modulator that prevents brain circuits from becoming overexcited. When specific MDGA1 mutations occur, the phosphorylation level of Synapsin II drops, impairing communication between neurons and destabilizing neural networks.
Using genetically modified mouse models, the investigators showed that MDGA1 mutations cause distinct outcomes in males and females. Male mice carrying the MDGA1 mutations displayed autism-like traits—including impaired ultrasonic vocalizations and sensorimotor gating deficits—whereas female mice did not show these behavioral deficits.
The researchers found that estrogen signaling in females provides a protective effect on neural circuits, buffering them against the functional consequences of MDGA1 disruption. Leveraging this protective mechanism, they treated male MDGA1-mutant mice with bazedoxifene, a selective estrogen receptor modulator already approved by the US Food and Drug Administration for other indications.
Bazedoxifene treatment restored the phosphorylation and expression patterns of several GABAergic synaptic proteins, improved synaptic strength, and normalized the autism-like behaviors observed in male mutant mice. The results suggest that modulating estrogen signaling could be a viable strategy to correct specific molecular deficits caused by MDGA1 mutations.
“This study is important because it identifies a new genetic factor linked to ASD and explains a molecular mechanism that produces sex differences,” said Professor Jaewon Ko. “Because bazedoxifene’s safety profile is already established, these findings open a more rapid path toward clinical evaluation as a targeted treatment for cases of ASD tied to MDGA1 dysfunction.”
Co-first authors include Seungjun Kim (now a postdoctoral researcher at Rutgers University) and Hyeonho Kim. The international team includes contributors from DGIST, Hospital Universitario Quironsalud (Spain), Korea Basic Science Institute, Korea Institute of Science and Technology, Korea University, KAIST, the University of Colorado, and others.
The full study was published online on March 20, 2026, in EMBO Molecular Medicine.
Funding: This work was supported by the Leader Research Program, the Mid-Career Researcher Support Program, and the Sejong Science Fellowship from the Ministry of Science and ICT and the National Research Foundation of Korea.
Key Questions Answered:
A: This phenomenon is consistent with the “female protective effect.” Female brains have higher baseline estrogen signaling, which helps stabilize neural circuits when MDGA1 function is compromised. Males lack this same level of estrogen-mediated protection, so circuit dysfunction manifests more readily.
A: Not a universal cure. The drug reversed specific molecular and behavioral abnormalities caused by MDGA1 mutations in mouse models. Because bazedoxifene is already approved for other uses, it could reach clinical trials for this molecular subtype of ASD more quickly than a novel compound.
A: No. ASD is genetically heterogeneous. MDGA1 mutations represent one of multiple possible genetic contributors. Nevertheless, this discovery helps explain broader biological patterns—particularly the sex bias observed in many ASD cases.
Editorial Notes:
- This article was edited by a Neuroscience News editor.
- The journal paper was reviewed in full.
- Additional context was provided by staff editors.
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 et al., published in EMBO Molecular Medicine. DOI and original paper details are cited in the journal publication.
Abstract
Bazedoxifene reverses sexually dimorphic autistic-like abnormalities in biallelic MDGA1-mutant mice
MDGA1 has been implicated in the suppression of GABAergic synaptic inhibition. The current study describes ASD patients with MDGA1 missense mutations and demonstrates that different mutations produce distinct dysfunctions in MDGA1 structure and function. In utero overexpression of one mutation altered cortical neuron migration and impaired ultrasonic vocalizations in mice. Another mutation disrupted MDGA1’s extracellular structure and its influence on GABAergic synapses.
Male MDGA1 knock-in and conditional knockout mice exhibited impaired ultrasonic vocalizations and sensorimotor gating, while female counterparts did not show behavioral deficits. Treatment of male mutant mice with bazedoxifene rescued changes in expression and phosphorylation of several GABAergic synaptic proteins, restored synaptic strength, and improved behavioral performance. These results indicate that MDGA1 mutations can cause ASD through sexually dimorphic loss- and gain-of-function mechanisms.