title: Autism-associated SHANK3 haploinsufficiency causes Ih channelopathy in human neurons.
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.
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 265 Campus Drive, Stanford, CA 94305, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Yi
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 265 Campus Drive, Stanford, CA 94305, USA. Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, 265 Campus Drive, Stanford, CA 94305, USA. Department of Pathology, Stanford University School of Medicine, 265 Campus Drive, Stanford, CA 94305, USA.
authors.forename: Tamas
authors.initials: T
authors.lastname: Danko
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 265 Campus Drive, Stanford, CA 94305, USA.
authors.forename: Salome Calado
authors.initials: SC
authors.lastname: Botelho
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 265 Campus Drive, Stanford, CA 94305, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Patzke
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, 265 Campus Drive, Stanford, CA 94305, USA.
authors.forename: ChangHui
authors.initials: C
authors.lastname: Pak
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, 265 Campus Drive, Stanford, CA 94305, USA. Department of Pathology, Stanford University School of Medicine, 265 Campus Drive, Stanford, CA 94305, USA.
authors.forename: Marius
authors.initials: M
authors.lastname: Wernig
authors.affiliation: 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. tcs1@stanford.edu.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Südhof
mesh_terms: D000200:Action Potentials; D000818:Animals; D000067877:Autism Spectrum Disorder / Q000235:genetics*; D002478:Cells, Cultured; D053447:Channelopathies / Q000235:genetics*; D002872:Chromosome Deletion; D025063:Chromosome Disorders / Q000235:genetics; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics; D053595:Embryonic Stem Cells / Q000378:metabolism; D017353:Gene Deletion; D005818:Genetic Engineering; D020022:Genetic Predisposition to Disease; D057895:Haploinsufficiency / Q000235:genetics*; D006801:Humans; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins; D016296:Mutagenesis; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D013569:Synapses / Q000502:physiology; D009435:Synaptic Transmission
chemical_list: D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; C492357:SHANK3 protein, human; C492356:Shank3 protein, mouse