SHANK3 overexpression causes manic-like behaviour with unique pharmacogenetic properties

Kihoon Han, J. Lloyd Holder, Christian P. Schaaf, Hui Lu, Hongmei Chen, Hyojin Kang, Jianrong Tang, Zhenyu Wu, Shuang Hao, Sau Wai Cheung, Peng Yu, Hao Sun, Amy M. Breman, Ankita Patel, Hui-Chen Lu and Huda Y. Zoghbi ()
Additional contact information
Kihoon Han: Baylor College of Medicine
J. Lloyd Holder: Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital
Christian P. Schaaf: Baylor College of Medicine
Hui Lu: Baylor College of Medicine
Hongmei Chen: Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital
Hyojin Kang: Baylor College of Medicine
Jianrong Tang: Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital
Zhenyu Wu: Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital
Shuang Hao: Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital
Sau Wai Cheung: Baylor College of Medicine
Peng Yu: Baylor College of Medicine
Hao Sun: Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital
Amy M. Breman: Baylor College of Medicine
Ankita Patel: Baylor College of Medicine
Hui-Chen Lu: Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital
Huda Y. Zoghbi: Baylor College of Medicine

Nature, 2013, vol. 503, issue 7474, 72-77

Abstract: 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.

Date: 2013
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DOI: 10.1038/nature12630

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