2. Academic Validation
  3. The novel role of GADD45A in the etiology of autism: modulating neuronal excitability via TET1/R-loop dependent regulation of KCNQ5

The novel role of GADD45A in the etiology of autism: modulating neuronal excitability via TET1/R-loop dependent regulation of KCNQ5

  • Mol Psychiatry. 2026 Jul;31(7):3786-3800. doi: 10.1038/s41380-026-03498-3.
Juncen Guo # 1 2,  Bin Zhu # 3,  Ying Zhang # 1 2,  Qing Li # 1 2,  Jing Zhang 1 2,  Qing He 4,  Juan Du 5,  Yuelin Song 1 2,  Tongtong Li 6,  Heng Yin 1 7,  Hanyun Que 1 2,  Jiangtao Li 1 2,  Sixian Wu 1 2,  Gelin Huang 1 2,  Zhiliang Ji 5,  Peng Xu 3,  Wenming Xu 8 9,  Tian Tang 10 11
Affiliations

Affiliations

  • 1 Department of Obstetrics/Gynecology, Joint Laboratory of Reproductive Medicine (SCU-CUHK), Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, 610041, China.
  • 2 Department of Obstetrics and Gynecology, Centre for Reproductive Medicine, West China Second University Hospital, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, 610041, China.
  • 3 School of Life Science and Technology, Center for Information in Medicine, University of Electronic Science and Technology of China, Chengdu, 611731, China.
  • 4 Guangyuan Central Hospital, Guangyuan, 628000, China.
  • 5 State Key Laboratory of Cellular Stress Biology, School of Life Sciences, Faculty of Medicine and Life Sciences, Xiamen University, Xiamen, Fujian, 361102, China.
  • 6 State Key Laboratory of Reproductive Medicine and Offspring Health, Center for Reproductive Medicine, Institute of Women, Children and Reproductive Health, Shandong University, Jinan, 250012, China.
  • 7 Chengdu Third People's Hospital, Chengdu, 610041, China.
  • 8 Department of Obstetrics/Gynecology, Joint Laboratory of Reproductive Medicine (SCU-CUHK), Key Laboratory of Obstetric, Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, 610041, China. [email protected].
  • 9 Department of Obstetrics and Gynecology, Centre for Reproductive Medicine, West China Second University Hospital, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, 610041, China. [email protected].
  • 10 Department of Obstetrics and Gynecology, Centre for Reproductive Medicine, West China Second University Hospital, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, Chengdu, 610041, China. [email protected].
  • 11 Sichuan Provincial Key Laboratory of Development and Related Diseases of Women and Children, West China Second University Hospital, Chengdu, 610041, Sichuan, China. [email protected].
  • # Contributed equally.
PMID: 41741708 DOI: 10.1038/s41380-026-03498-3
Abstract

The etiology of autism currently includes prenatal exposure factors and genetic variants, but it remains unclear how these factors converge on a common pathway. Through multiple autism transcriptome analyses of public data, we discovered that the disruption of Gadd45a may explain the pathogenesis of various types of autism, including the most established valproic acid (VPA) prenatal exposure and MECP2 gene-related autism. Subsequently, we generated Gadd45a knockout mice and found that these mice exhibit significant deficits in social ability, as well as autistic-like phenotypes such as increased digging behaviors. We demonstrated the preferential expression of Gadd45a in cortical excitatory neurons. Through in vivo electrophysiological recordings, we found that the firing frequency of excitatory neurons in the medial prefrontal cortex of knockout mice is abnormal in both resting and task states, which may explain the autistic-like phenotypes exhibited by these mice. Remarkably, we revealed that abnormal neuron firing may be due to the failure of TET1, a GADD45A-interacting protein, to be recruited to the promoter region of Kcnq5, thereby preventing normal DNA demethylation and transcription initiation in the absence of GADD45A. We also demonstrated that GADD45A can recognize R-loop structure to recruit TET1 to the CpG islands of KCNQ5 and regulate the transcription level of KCNQ5. This process also involved nearby antisense lncRNA in the formation of R-loops. Our study revealed a hub gene, GADD45A, and its epigenetic regulation of ion channels (GADD45A/TET1-KCNQ5 axis), which plays a critical role in the pathogenesis of autism.

Figures
Products