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Mol. Psychiatr., Oct 31 2025, | https://doi.org/10.1038/s41380-025-03313-5
Autism-associated ARHGEF9 variants impair GABAergic synapses and ultrasonic communication by reducing gephyrin phosphorylation
Hyeji Jung1,2, Byeongchan Kim1, Gyubin Jang1,2, Hyojung Lee1, Younghye Kim1,2, Hyeonho Kim1,2, Hea Ji Lee3, Dongwook Kim1,2, Yeji Yang3,4, Woo Chan Jeong1, Seungjoon Kim1,2, Ah-reum Han5, Ho Min Kim4,5, Theofilos Papadopoulos6, Benjamin Durand7, Christine Francannet8, Amélie Piton9,10,11, Jin Young Kim3,12, Jaewon Ko1,2 and Ji Won Um1,2
1Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), 333 Techno Jungangdae-Ro, Hyeonpoong-Eup, Dalseong-Gun, Daegu 42988, Korea.
2Center for Synapse Diversity and Specificity, DGIST, Daegu 42988, Korea.
3Digital Omics Research Center, Korea Basic Science Institute (KBSI), Ochang 28119, Korea.
4Department of Biological Sciences, Korea Advanced Institute for Science and Technology (KAIST), Daejeon 34141, Korea.
5Center for Biomolecular and Cellular Structure, Institute for Basic Science (IBS), Daejeon 34126, Korea.
6Department of Molecular Neurobiology, Max Planck Institute for Multidisciplinary Sciences (City-Campus), Göttingen, Germany.
7Service de Génétique Médicale, Hôpitaux Universitaire de Strasbourg, Strasbourg, France.
8Service de Génétique Médicale, CHU Estaing, Clermont Ferrand, France.
9Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS UMR 7104– INSERM U1258 Illkirch-Graffenstaden, Illkirch-Graffenstaden, France.
10Laboratoire de Diagnostic Génétique, Institut de Génétique Médicale d’Alsace (IGMA), Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
11Institut Universitaire de France, Paris, France.
12Critical Diseases Diagnostics Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea.
Corresponding authors
Correspondence to Jin Young Kim, Jaewon Ko or Ji Won Um.
1Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology (DGIST), 333 Techno Jungangdae-Ro, Hyeonpoong-Eup, Dalseong-Gun, Daegu 42988, Korea.
2Center for Synapse Diversity and Specificity, DGIST, Daegu 42988, Korea.
3Digital Omics Research Center, Korea Basic Science Institute (KBSI), Ochang 28119, Korea.
4Department of Biological Sciences, Korea Advanced Institute for Science and Technology (KAIST), Daejeon 34141, Korea.
5Center for Biomolecular and Cellular Structure, Institute for Basic Science (IBS), Daejeon 34126, Korea.
6Department of Molecular Neurobiology, Max Planck Institute for Multidisciplinary Sciences (City-Campus), Göttingen, Germany.
7Service de Génétique Médicale, Hôpitaux Universitaire de Strasbourg, Strasbourg, France.
8Service de Génétique Médicale, CHU Estaing, Clermont Ferrand, France.
9Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS UMR 7104– INSERM U1258 Illkirch-Graffenstaden, Illkirch-Graffenstaden, France.
10Laboratoire de Diagnostic Génétique, Institut de Génétique Médicale d’Alsace (IGMA), Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
11Institut Universitaire de France, Paris, France.
12Critical Diseases Diagnostics Convergence Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea.
Corresponding authors
Correspondence to Jin Young Kim, Jaewon Ko or Ji Won Um.
Abstract
Missense and truncating variants of the X-chromosome-linked ARHGEF9 gene encoding collybistin (Cb) cause intellectual disability and epilepsy. Here we report novel rare variants in ARHGEF9 identified via exome sequencing in male individuals with autism spectrum disorders (ASD). Functional analyses revealed that p.R290C promotes abnormal gephyrin clustering in COS-7 cells and reduces inhibitory synapse density in cultured hippocampal neurons. Electrophysiological recordings revealed that p.V374F and p.G485S, in conjunction with p.R290C, induce defective inhibitory synaptic transmission. Furthermore, only the p.G485S markedly decreased phosphatidylinositol 3-phosphate-binding activity. Mice with conditional knockout (cKO) of Cb displayed altered inhibitory synaptic density and transmission in the medial prefrontal cortex (mPFC). Moreover, ultrasonic vocalization was impaired in mPFC-specific Cb-cKO mice. Strikingly, proteomic analyses showed that mPFC-specific Cb-cKO reduced gephyrin phosphorylation levels. Expression of a subset of ASD-associated ARHGEF9 variants failed to rescue impaired GABAergic synaptic transmission and reduced gephyrin phosphorylation levels in mPFC-specific Cb-cKO mice. Our data suggest that perturbation of diverse facets of Cb activity potentially triggers the onset and/or progression of ASDs via inducing altered balance in gephyrin phosphorylation.
논문정보
- Research article
- 2025년 10월 (BRIC 등록일 2025-11-03)
- 국내(교신)+국외 연구진
- 생명과학 > 신경생물학
관련 보도자료
자폐 환자는 왜 소통이 힘들까? DGIST가 뇌 속 답을 찾았다!
DGIST(총장 이건우) 뇌과학과 엄지원․고재원 교수 연구팀은 한국기초과학지원연구원(KBSI) 김진영 박사 연구팀과의 협업으로 자폐증 환자에게서 발견된 콜리비스틴(collybistin) 단백질의 돌연변이가 뇌의 억제성 시냅스 기능을 약화시키고, 의사소통 결핍을 일으키는 원인임을 규명했다. 이번 연구 결과는 자폐의 발병 원인을 분자 수준에서 밝히고, 향후 자폐 스펙트럼 장애 및 다양한 정신질환의 치료제 개발에 중요한 단서를 제시할 것으로 기대된다.
- Bio통신원
- 2025. 11. 10
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