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Nature. 2013 Nov 7;503(7474):72-7. doi: 10.1038/nature12630. Epub 2013 Oct 23.

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

Author information

1
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.

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.

PMID:
24153177
PMCID:
PMC3923348
DOI:
10.1038/nature12630
[Indexed for MEDLINE]
Free PMC Article

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