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Updated: Sep 16, 2025

Identification and Classification of Position-specific GABAA Receptor Subunit Missense Variants for Their Role In Hippocampal Pyramidal Neurons
Published on: June 6, 2025
Impact of Genetic Variants Associated with Neurodevelopmental Disorders on the WAVE Regulatory Complex
Song Xie1,2, Ke Zuo1,3,4, Silvia De Rubeis5,6,7,8,9,10
1Computational Biomedicine, Institute of Neuroscience and Medicine INM-9, Forschungszentrum Jülich GmbH, 52428Jülich, Germany.
Abstract:
The WAVE regulatory complex (WRC) is a heteropentamer necessary for the regulation of actin cytoskeleton. Genetic variants in components of the WRC have been associated with increased risk for neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD). Some of the missense variants associated with NDDs have been reported to cause aberrant detachment of the WRC domain active C-terminal region (ACR). Using molecular dynamics simulations, we show that these variants cause a similar increase in disorder in a specific helix of ACR as well as a decrease in ACR/WRC interactions, irrespective of their position and chemical nature. These might assist ACR detachment. We further demonstrate their impact on the large-scale motions of the complex. Taken together, these results do suggest that different modifications associated with the NDD-associated variants converge on similar changes to the structural dynamics of the WRC.
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