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Author (up) Yi, F.; Danko, T.; Botelho, S.C.; Patzke, C.; Pak, C.H.; Wernig, M.; Sudhof, T.C. url  doi
  Title Autism-associated SHANK3 haploinsufficiency causes Ih channelopathy in human neurons Type Journal Article
  Year 2016 Publication Science (New York, N.Y.) Abbreviated Journal Science  
  Volume 352 Issue 6286 Pages aaf2669  
  Keywords Action Potentials; Animals; Autism Spectrum Disorder/*genetics; Cells, Cultured; Channelopathies/*genetics; Chromosome Deletion; Chromosome Disorders/genetics; Chromosomes, Human, Pair 22/genetics; Embryonic Stem Cells/metabolism; Gene Deletion; Genetic Engineering; *Genetic Predisposition to Disease; Haploinsufficiency/*genetics; Humans; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels/metabolism; Mice; Mice, Knockout; Mutagenesis; Nerve Tissue Proteins/*genetics/metabolism; Neurons/*metabolism; Synapses/physiology; Synaptic Transmission  
  Abstract Heterozygous SHANK3 mutations are associated with idiopathic autism and Phelan-McDermid syndrome. SHANK3 is a ubiquitously expressed scaffolding protein that is enriched in postsynaptic excitatory synapses. Here, we used engineered conditional mutations in human neurons and found that heterozygous and homozygous SHANK3 mutations severely and specifically impaired hyperpolarization-activated cation (Ih) channels. SHANK3 mutations caused alterations in neuronal morphology and synaptic connectivity; chronic pharmacological blockage of Ih channels reproduced these phenotypes, suggesting that they may be secondary to Ih-channel impairment. Moreover, mouse Shank3-deficient neurons also exhibited severe decreases in Ih currents. SHANK3 protein interacted with hyperpolarization-activated cyclic nucleotide-gated channel proteins (HCN proteins) that form Ih channels, indicating that SHANK3 functions to organize HCN channels. Our data suggest that SHANK3 mutations predispose to autism, at least partially, by inducing an Ih channelopathy that may be amenable to pharmacological intervention.  
  Address Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 265 Campus Drive, Stanford, CA 94305, USA. Howard Hughes Medical Institute, Stanford University School of Medicine, 265 Campus Drive, Stanford, CA 94305, USA.  
  Corporate Author Thesis  
  Publisher Place of Publication Editor  
  Language English Summary Language Original Title  
  Series Editor Series Title Abbreviated Series Title  
  Series Volume Series Issue Edition  
  ISSN 0036-8075 ISBN Medium  
  Area Expedition Conference  
  Notes PMID:26966193 Approved no  
  Call Number ref @ user @ Serial 95969  
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