LAUSR

Missense variants in UBE3A underlie neurodevelopmental conditions such as Angelman Syndrome and Autism Spectrum Disorder, but the underlying molecular pathological consequences on protein folding and function are poorly understood. Here, we report a novel, maternally inherited, likely pathogenic missense variant in UBE3A (NM_000462.4(UBE3A_v001):(c.1841T>C) (p.(Leu614Pro))) in a child that presented with myoclonic epilepsy from 14 months, subsequent developmental regression from 16 months, and additional features consistent with Angelman Syndrome. To understand the impact of p.(Leu614Pro) on UBE3A, we used adiabatic biased molecular dynamics and metadynamics simulations to investigate conformational differences from wildtype proteins. Our results suggest that Leu614Pro substitution leads to less efficient binding and substrate processing compared to wildtype. Our results support the use of enhanced sampling molecular simulations to investigate the impact of missense UBE3A variants on protein function that underlies neurodevelopment and human disorders.