title: SHANK3 overexpression causes manic-like behaviour with unique pharmacogenetic properties.
abstract: 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.
authors.affiliation: 1] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA [2] Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas 77030, USA [3] Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas 77030, USA.
authors.forename: Kihoon
authors.initials: K
authors.lastname: Han
authors.forename: J Lloyd
authors.initials: JL
authors.lastname: Holder
authors.forename: Christian P
authors.initials: CP
authors.lastname: Schaaf
authors.forename: Hui
authors.initials: H
authors.lastname: Lu
authors.forename: Hongmei
authors.initials: H
authors.lastname: Chen
authors.forename: Hyojin
authors.initials: H
authors.lastname: Kang
authors.forename: Jianrong
authors.initials: J
authors.lastname: Tang
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Wu
authors.forename: Shuang
authors.initials: S
authors.lastname: Hao
authors.forename: Sau Wai
authors.initials: SW
authors.lastname: Cheung
authors.forename: Peng
authors.initials: P
authors.lastname: Yu
authors.forename: Hao
authors.initials: H
authors.lastname: Sun
authors.forename: Amy M
authors.initials: AM
authors.lastname: Breman
authors.forename: Ankita
authors.initials: A
authors.lastname: Patel
authors.forename: Hui-Chen
authors.initials: HC
authors.lastname: Lu
authors.forename: Huda Y
authors.initials: HY
authors.lastname: Zoghbi
mesh_terms: D051376:Actin-Related Protein 2-3 Complex / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000328:Adult; D000818:Animals; D001522:Behavior, Animal; D001714:Bipolar Disorder / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology*; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics; D004195:Disease Models, Animal; D019706:Excitatory Postsynaptic Potentials; D005260:Female; D018628:Gene Dosage / Q000235:genetics; D015870:Gene Expression / Q000235:genetics; D020131:Genes, Duplicate / Q000235:genetics; D006801:Humans; D006948:Hyperkinesis / Q000235:genetics / Q000503:physiopathology; D053444:Inhibitory Postsynaptic Potentials; D008094:Lithium / Q000494:pharmacology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D012640:Seizures / Q000235:genetics; D014635:Valproic Acid / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D051376:Actin-Related Protein 2-3 Complex; D000199:Actins; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; C492356:Shank3 protein, mouse; D014635:Valproic Acid; D008094:Lithium