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SHANK3 overexpression causes manic-like behaviour with unique pharmacogenetic properties.

Nature | Nov 7, 2013

Mutations in SHANK3 and large duplications of the region spanning SHANK3 both cause a spectrum of neuropsychiatric disorders, indicating that proper SHANK3 dosage is critical for normal brain function. However, SHANK3 overexpression per se has not been established as a cause of human disorders because 22q13 duplications involve several genes. Here we report that Shank3 transgenic mice modelling a human SHANK3 duplication exhibit manic-like behaviour and seizures consistent with synaptic excitatory/inhibitory imbalance. We also identified two patients with hyperkinetic disorders carrying the smallest SHANK3-spanning duplications reported so far. These findings indicate that SHANK3 overexpression causes a hyperkinetic neuropsychiatric disorder. To probe the mechanism underlying the phenotype, we generated a Shank3 in vivo interactome and found that Shank3 directly interacts with the Arp2/3 complex to increase F-actin levels in Shank3 transgenic mice. The mood-stabilizing drug valproate, but not lithium, rescues the manic-like behaviour of Shank3 transgenic mice raising the possibility that this hyperkinetic disorder has a unique pharmacogenetic profile.

Pubmed ID: 24153177 RIS Download

Mesh terms: Actin-Related Protein 2-3 Complex | Actins | Adult | Animals | Behavior, Animal | Bipolar Disorder | Chromosomes, Human, Pair 22 | Disease Models, Animal | Excitatory Postsynaptic Potentials | Female | Gene Dosage | Gene Expression | Genes, Duplicate | Humans | Hyperkinesis | Inhibitory Postsynaptic Potentials | Lithium | Male | Mice | Mice, Transgenic | Nerve Tissue Proteins | Seizures | Valproic Acid

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Associated grants

  • Agency: NINDS NIH HHS, Id: 1R01NS070302
  • Agency: NINDS NIH HHS, Id: 2T32NS043124
  • Agency: NINDS NIH HHS, Id: R01 NS048884
  • Agency: NICHD NIH HHS, Id: P30 HD024064
  • Agency: Howard Hughes Medical Institute, Id: T32 NS043124
  • Agency: NINDS NIH HHS, Id: P30HD024064
  • Agency: NICHD NIH HHS, Id: R01 NS070302
  • Agency: NINDS NIH HHS, Id:

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Interaction Reference Index

An index of protein interactions available in a number of primary interaction databases including BIND, BioGRID, CORUM, DIP, HPRD, IntAct, MINT, MPact, MPPI and OPHID. This index includes multiple interaction types including physical and genetic (mapped to their corresponding protein products) as determined by a multitude of methods. This index allows the user to search for a protein and retrieve a non-redundant list of interactors for that protein. iRefIndex uses the Sequence Global Unique Identifier (SEGUID) to group proteins and interactions into redundant groups. This method allows users to integrate their own data with the iRefIndex in a way that ensures proteins with the exact same sequence will be represented only once. iRefIndex project has three long term objectives: # to facilitate exchange of interaction data between interaction databases. # to consolidate interaction data from multiple sources. # to provide feedback to source interaction databases. iRefIndex is made available in a number of formats: MITAB tab-delimited text files, iRefWeb interface, iRefScape plugin for Cytoscape, PSICQUIC Web services, and an interface for the R programming language environment.

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