Abstract
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.
Highlights
The identification of neuropsychiatric genetic variants has increased and proved challenging in autism spectrum disorder (ASD), where several genes are implicated
To more efficiently understand the impact of missense variants associated with ASD, we developed and validated an in vivo approach that can assess the effect of a variant in GABAergic cortical interneurons (CINs; Vogt et al, 2015a, 2018)
We chose five human (h)TSC1 variants based on their previous association with an ASD diagnosis (Schaaf et al, 2011; Kelleher et al, 2012); R336W, T360N, T393I, S403L, and H732Y, and subcloned them into a lentiviral DNA vector (Figure 1A, top)
Summary
The identification of neuropsychiatric genetic variants has increased and proved challenging in autism spectrum disorder (ASD), where several genes are implicated. While the functional impact of some variants can be easy to predict, i.e., loss of function, frameshift, and nonsense, the effect of missense variants has been challenging to predict and validate. An ideal method to validate these variants could be to generate a knock-in model for each, which provides an in vivo environment for cells to develop. This is costly, time-consuming, and inefficient, making it challenging to study variants in vivo. To more efficiently understand the impact of missense variants associated with ASD, we developed and validated an in vivo approach that can assess the effect of a variant in GABAergic cortical interneurons (CINs; Vogt et al, 2015a, 2018)
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