The TSC1 and TSC2 genes are connected to multiple syndromes from Tuberous Sclerosis Complex (TSC) to autism spectrum disorder (ASD), with uncertainty if genetic variants cause all or subsets of phenotypes based on the location and type of change. For TSC1, few have addressed if non-TSC associated genetic variants have direct contributions to changes in neurological genotype-to-phenotype impacts, including elevated rates of ASD and seizures. Dominant variants cause TSC, yet TSC1 has many heritable variants not dominant for TSC that are poorly understood in neurological function, with some associated with ASD. Herein, we examined how missense variants in TSC1, R336W, T360N, T393I, S403L, and H732Y, impacted the development of cortical inhibitory interneurons, cell-types whose molecular, cellular, and physiological properties are altered after the loss of mouse TSC1. We found these variants complemented a known phenotype caused by loss of TSC1, increased cell size. However, distinct variants, particularly S403L showed deficits in complementing an increase in parvalbumin levels and exhibited smaller amplitude after hyperpolarizations. Overall, these data show that subtle phenotypes can be induced by some TSC1 missense variants and provide an in vivo system to assess TSC1 variants’ neurological impact better.

的 TSC1 和 TSC2这些基因与结节性硬化症（TSC）到自闭症谱系障碍（ASD）的多种综合症有关，根据变化的位置和类型，遗传变异是否会导致全部或部分表型尚不确定。对于TSC1，几乎没有人解决非TSC相关的遗传变异是否直接改变了神经基因型对表型的影响，包括升高的ASD和癫痫发作率。主要变体会导致TSC，TSC1具有许多在TSC方面不占优势的可遗传变异，在神经功能上了解甚少，其中一些与ASD相关。在这里，我们研究了TSC1，R336W，T360N，T393I，S403L和H732Y影响了皮层抑制性中间神经元的发展，这些神经元是在小鼠丢失后分子，细胞和生理特性发生改变的细胞类型 TSC1。我们发现这些变异补充了已知的表型缺失TSC1，增加单元格大小。但是，不同的变体，特别是S403L，在补充小白蛋白水平增加时显示出不足，并且在超极化后表现出较小的振幅。总体而言，这些数据表明，一些人可以诱导出细微的表型。TSC1 错义变体并提供 体内 评估系统 TSC1 变种的神经学影响更好。