PDF(Pubmed)
Abstract：
The SH3 and multiple ankyrin repeat domains (SHANKs) are a family of scaffolding proteins located in excitatory synapses required for their development and function. Molecular defects of SHANK3 are a well-known cause of several neurodevelopmental entities, in particular autism spectrum disorders and epilepsy, whereas relatively little is known about disease associations of SHANK1. Here, we propose a novel de novo mosaic p.(Gly126Arg) SHANK1 variant as the monogenic cause of disease in a patient who presented, from the age of 2 years, moderate intellectual disability, autism, and refractory epilepsy of the Lennox-Gastaut type. The epilepsy responded remarkably well to cannabidiol add-on therapy. In silico analyses including homology modeling and molecular dynamics simulations indicated the deleterious effect of SHANK1 p.(Gly126Arg) on the protein structure and the related function associated with protein-protein interactions. In particular, the variant was predicted to disrupt a hitherto unknown conserved region of SHANK1 protein with high homology to a recently recognized functionally relevant domain in SHANK3 implicated in ligand binding, including the \"non-canonical\" binding of Rap1.
摘要：
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