莱布尼茨分子药理学研究所Noa Lipstein课题组在研究中取得进展。他们发现了致病性UNC13A变异通过损害突触功能引起神经发育综合征。2025年10月22日出版的《自然—遗传学》杂志发表了这项成果。

在这里，小组描述了一种由种系编码或UNC13A剪接位点变异引起的神经发育综合征。该综合征表现为不同程度的发育迟缓和智力残疾、不同类型的癫痫发作、震颤和运动障碍，在某些情况下，幼儿期死亡。通过对无主题海马神经元和秀丽隐杆线虫中UNC13A变异体表达的检测，研究团队确定了三种致病机制，包括由UNC13A蛋白表达减少引起的突触强度降低，由UNC13A功能获得引起的神经传递增加，以及第二信使信号传导调节受损。基于强烈的基因型-表型-功能相关性，该课题组人员将UNC13A综合征分为三种亚型（A–C型）。课题组人员得出结论，UNC13A对神经递质释放的精确调控对人类神经系统功能至关重要。

研究人员表示，UNC13A基因编码一种突触前蛋白，这种蛋白对于设置神经元之间信息传递的强度和动态至关重要。

附：英文原文

Title: Pathogenic UNC13A variants cause a neurodevelopmental syndrome by impairing synaptic function

Author: Asadollahi, Reza, Ahmad, Aisha, Boonsawat, Paranchai, Shahanoor Hinzen, Jasmine, Lohse, Mareike, Bouazza-Arostegui, Boris, Sun, Siqi, Utesch, Tillmann, Sommer, Jonas D., Ilic, Dragana, Padmanarayana, Murugesh, Fischermanns, Kati, Ranjan, Mrinalini, Boll, Moritz, Ka, Chandran, Piton, Amlie, Mattioli, Francesca, Isidor, Bertrand, unap, Katrin, Reinson, Karit, Wojcik, Monica H., Marshall, Christian R., Mercimek-Andrews, Saadet, Matsumoto, Naomichi, Miyake, Noriko, Stephan, Bruno de Oliveira, Honjo, Rachel Sayuri, Bertola, Debora R., Kim, Chong Ae, Yusupov, Roman, Mefford, Heather C., Christodoulou, John, Lee, Joy, Heath, Oliver, Brown, Natasha J., Baker, Naomi, Stark, Zornitza, Delatycki, Martin, Lake, Nicole J., Zeidler, Shimriet, Zuurbier, Linda, Maas, Saskia M., de Kruiff, Chris C., Rajabi, Farrah, Rodan, Lance H., Coury, Stephanie A., Platzer, Konrad, Oppermann, Henry, Abou Jamra, Rami, Beblo, Skadi, Maxton, Caroline, migiel, Robert, Underhill, Hunter, Dubbs, Holly, Rosen, Alyssa, Helbig, Katherine L., Helbig, Ingo, Ruggiero, Sarah McKeown, Fitzgerald, Mark P., Kraemer, Dennis, Prada, Carlos E., Tenney, Jeffrey

Issue&Volume: 2025-10-22

Abstract: The UNC13A gene encodes a presynaptic protein that is crucial for setting the strength and dynamics of information transfer between neurons. Here we describe a neurodevelopmental syndrome caused by germline coding or splice-site variants in UNC13A. The syndrome presents with variable degrees of developmental delay and intellectual disability, seizures of different types, tremor and dyskinetic movements and, in some cases, death in early childhood. Using assays with expression of UNC13A variants in mouse hippocampal neurons and in Caenorhabditis elegans, we identify three mechanisms of pathogenicity, including reduction in synaptic strength caused by reduced UNC13A protein expression, increased neurotransmission caused by UNC13A gain-of-function and impaired regulation of neurotransmission by second messenger signalling. Based on a strong genotype–phenotype-functional correlation, we classify three UNC13A syndrome subtypes (types A–C). We conclude that the precise regulation of neurotransmitter release by UNC13A is critical for human nervous system function.

DOI: 10.1038/s41588-025-02361-5

Source: https://www.nature.com/articles/s41588-025-02361-5