Zhao Na, Xiong Qiuhong, Li Ping, Chen Guangxin, Xiao Han, Wu Changxin
Key Laboratory of Chemical Biology and Molecular Engineering of National Ministry of Education, Institutes of Biomedical Sciences, Shanxi University, Taiyuan, 030006, China.
Department of Pathology, The Second Hospital of ShanXi Medical University, No.382 WuYi Road, Tai Yuan, ShanXi, Taiyuan, 030000, China.
Sci Rep. 2025 Jan 13;15(1):1892. doi: 10.1038/s41598-025-85706-8.
The TSC complex formed by TSC1 and TSC2 is the most important upstream negative regulator of mTORC1. Genetic variations in either TSC1 or TSC2 cause tuberous sclerosis complex (TSC) disease which is a rare autosomal dominant disorder resulting in impairment of multiple organ systems. In this study, besides a reported variation, c.2509_2512del (p.Asn837Valfs11, p.N837fs) in TSC1, we found a de novo TSC2 variation c.1113delG (p.Gln371Hisfs18, p.Q371fs), which these two mutation influence the formation of TSC complex. We found that the decrease of TSC complex with the appearance of the decreased miR-199b-3p expression. At the same time, the reduction of miR-199b-3p increased the expression of mTOR and the activation of mTORC1 and mTORC2, the additional miR-199b-3p caused the decrease the expression of mTOR and the activation of mTORC1 and mTORC2. In brief, our results may illustrate a novel mechanism of TSC caused by variations in either TSC1 or TSC2, and a new mTOR expression regulator, miR-199b-3p.
由TSC1和TSC2形成的TSC复合物是mTORC1最重要的上游负调控因子。TSC1或TSC2中的基因变异会导致结节性硬化症（TSC），这是一种罕见的常染色体显性疾病，会导致多个器官系统受损。在本研究中，除了报道的TSC1变异c.2509_2512del（p.Asn837Valfs11，p.N837fs）外，我们还发现了一个新的TSC2变异c.1113delG（p.Gln371Hisfs18，p.Q371fs），这两种突变都会影响TSC复合物的形成。我们发现随着miR-199b-3p表达的降低，TSC复合物也减少。同时，miR-199b-3p的减少会增加mTOR的表达以及mTORC1和mTORC2的激活，而额外添加miR-199b-3p则会导致mTOR表达降低以及mTORC1和mTORC2的激活。简而言之，我们的结果可能阐明了由TSC1或TSC2变异引起的TSC的一种新机制，以及一种新的mTOR表达调节因子miR-199b-3p。
