| First Author | Han K | Year | 2013 |
| Journal | Nature | Volume | 503 |
| Issue | 7474 | Pages | 72-7 |
| PubMed ID | 24153177 | Mgi Jnum | J:201867 |
| Mgi Id | MGI:5515939 | Doi | 10.1038/nature12630 |
| Citation | Han K, et al. (2013) SHANK3 overexpression causes manic-like behaviour with unique pharmacogenetic properties. Nature 503(7474):72-7 |
| abstractText | 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. |
