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.
33Tuberous Sclerosis Complex is a complex syndrome that affects multiple organs and is caused 34 by dysfunction of either the TSC1 or TSC2 genes. One of the least understood features of TSC 35is the impact of TSC1&2 variants on brain phenotypes, including elevated rates of autism 36 spectrum disorder and seizures. Moreover, while a great deal of work has uncovered how loss of 37 either gene can alter various neural cell types, the impact of many variants in TSC and on these 38 cell types is poorly understood. In particular, missense variants that cause minor changes in the 39proteins are expected to cause functional changes that differ from a complete loss of the protein. 40Herein, we examined how some missense variants in TSC1 impacted the development of cortical 41 inhibitory interneurons, a cell type whose molecular, cellular and physiological properties are 42 known to be altered after loss of mouse Tsc1. Importantly, we found that most missense variants 43 complemented phenotypes caused by loss of Tsc1 and resulting in elevated MTOR activity as 44well as several cell intrinsic physiological properties. However, distinct variants showed deficits in 45complementing an increase in parvalbumin levels, which is observed after loss of Tsc1 and 46 demonstrated smaller amplitudes of after hyperpolarizations. These data suggest subtle but 47 sensitive phenotypes can be detected by some TSC1 missense variants and provide an in vivo 48 system in which to better assess TSC variants. 49 50
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