PDF(Pubmed)
Abstract：
The mechanistic target of rapamycin (mTOR) pathway serves as a master regulator of cell growth, proliferation, and survival. Upregulation of the mTOR pathway has been shown to cause malformations of cortical development, medically refractory epilepsies, and neurodevelopmental disorders, collectively described as mTORopathies. Tuberous sclerosis complex (TSC) serves as the prototypical mTORopathy. Characterized by the development of benign tumors in multiple organs, pathogenic variants in TSC1 or TSC2 disrupt the TSC protein complex, a negative regulator of the mTOR pathway. Variants in critical domains of the TSC complex, especially in the catalytic TSC2 subunit, correlate with increased disease severity. Variants in less crucial exons and non-coding regions, as well as those undetectable with conventional testing, may lead to milder phenotypes. Despite the assumption of complete penetrance, expressivity varies within families, and certain variants delay disease onset with milder neurological effects. Understanding these genotype-phenotype correlations is crucial for effective clinical management. Notably, 15% of patients have no mutation identified by conventional genetic testing, with the majority of cases postulated to be caused by somatic TSC1/TSC2 variants which present complex diagnostic challenges. Advancements in genetic testing, prenatal screening, and precision medicine hold promise for changing the diagnostic and treatment paradigm for TSC and related mTORopathies. Herein, we explore the genetic and molecular mechanisms of TSC and other mTORopathies, emphasizing contemporary genetic methods in understanding and diagnosing the condition.
摘要：
雷帕霉素（mTOR）途径的机制靶标作为细胞生长的主要调节因子，扩散,和生存。mTOR通路的上调已被证明会导致皮质发育的畸形，药物难治性癫痫，和神经发育障碍，统称为mTORopathies。结节性硬化症（TSC）是典型的mTORopathy。以多个器官良性肿瘤的发展为特征，TSC1或TSC2的致病变体破坏TSC蛋白复合物，mTOR通路的负调节因子。TSC复合体关键域的变体，特别是在催化TSC2亚基中，与疾病严重程度增加相关。不太重要的外显子和非编码区的变异，以及那些传统测试无法检测到的，可能导致更温和的表型。尽管假设是完全外显率，家庭内部的表现力各不相同，和某些变异延迟疾病的发作与较温和的神经影响。了解这些基因型-表型相关性对于有效的临床管理至关重要。值得注意的是,15%的患者通过常规基因检测没有发现突变，大多数病例被认为是由存在复杂诊断挑战的体细胞TSC1/TSC2变异引起的。基因检测的进步，产前筛查,精准医学有望改变TSC和相关mTORopathies的诊断和治疗范式。在这里，我们探索了TSC和其他mTORopathies的遗传和分子机制，强调当代遗传方法在理解和诊断条件。
