Autism-associated SHANK3 haploinsufficiency causes I h channelopathy in human neurons

Abstract

Faulty channels, not faulty synapses SHANK3 is a widely expressed scaffolding protein that is enriched in postsynaptic specializations. In mutant mice, SHANK3 mutations cause autism-like behavioral changes and exhibit alterations in synaptic transmission. Yi et al. produced human neurons lacking SHANK3 but not other genes that are also involved in the autism-like disease Phelan-McDermid syndrome. Instead of affecting synapses, SHANK3 mutations primarily caused a channelopathy, with the major phenotype consisting of a specific impairment of HCN channels. Chronic impairment of membrane currents through channelopathy could account for the phenotypes observed in Phelan-McDermid neurons, such as alterations in cognitive functions and the predisposition to epilepsy. Science , this issue p. 10.1126/science.aaf2669