X-linked SYTL4 missense variant disrupts RAB27A-dependent vesicle trafficking and synaptic transmission in autism

• 成果类型: Article
• 署名作者: Liao, Yang; Zhang, Shuju; Zhang, Xiaolei; Tan, Senwei; Luo, Yu; Wan, Yingjie; Lyu, Yongqing; Xie, Boyuan; Zhan, Rui; Zhang, Yu; Chen, Guodong; Jia, Xiangbin; Hu, Zhengmao; Zheng, Yu; Mao, Xiao; Wang, Hua; Tan, Jieqiong; Li, Faxiang; Peng, Yu; Xia, Kun; Guo, Hui
• 署名单位: Central South University; Central South University; Furong Laboratory
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2605483123
• 发表日期: 2026-08-04
• 页码: e2605483123
• 关键词: autism; SYTL4; Rab27a; vesicle trafficking; synaptic transmission; RAB27A EFFECTORS; identification; hippocampal; GRANUPHILIN; exocytosis; behaviors; interplay

摘要

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by impaired social communication and repetitive behaviors, with genetic studies implicating widespread synaptic dysfunction. However, the contribution of presynaptic vesicle trafficking mechanisms to ASD pathogenesis remains incompletely understood. Here, we identify synaptotagmin-like protein 4 (SYTL4), a RAB27A effector previously characterized in secretory cells, as a regulator of presynaptic function in the mammalian brain. We report a recurrent hemizygous missense variant, R126H, located within the Rab-binding domain of SYTL4 in four unrelated male individuals, consistent with an X-linked recessive mode of ASD, and additionally identify a de novo missense variant in RAB27A (T41A) in an independent ASD family that affects a domain mediating interactions with downstream effectors. Using a R126H knock-in mouse model, we show that R126H knock-in male mice exhibit ASD-relevant behavioral abnormalities accompanied by synaptic deficits in the medial prefrontal cortex. At the molecular level, ASD-associated SYTL4 and RAB27A variants interfere with the interaction between SYTL4 and RAB27A, providing a mechanistic link between human genetic variation and synaptic dysfunction. Together, these findings implicate disrupted SYTL4-RAB27A-dependent vesicle trafficking in ASD pathogenesis and identify SYTL4 and RAB27A as previously unrecognized contributors to autism-associated synaptic deficits and behavior.