Channel scaffolding and its contribution to SCN2A disorders

Awardee: Paul Jenkins

Institution: University of Michigan Medical School

Grant Amount: $61,280.00

Funding Period: February 1, 2024 - January 31, 2025

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Summary:

Thanks to critical genomic data like the Simons Simplex Collection, the scientific community possesses dozens of highly reliable risk genes through the identification of rare de novo variants in patients with autism spectrum disorder (ASD). Loss-of-function in SCN2A, which encodes the neuronal sodium channel NaV1.2, has one of the strongest ASD associations . A large number of SCN2A variants have been shown to alter channel biophysical properties contributing to deficits in electrical signaling within the brain. Strikingly, a significant number of SCN2A variants have little to no detectable effect on channel functional properties, suggesting they are contributing to disease etiology through alternative mechanisms. In this proposal, we will test the hypothesis that these variants contribute to disease phenotypes by disrupting normal channel scaffolding causing channel mislocalization and neuronal dysfunction.