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Published on: November 2, 2020
SHANK3 overexpression causes manic-like behaviour with unique pharmacogenetic properties
Kihoon Han1, J Lloyd Holder, Christian P Schaaf
11] 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.
SHANK3 gene overexpression causes hyperkinetic neuropsychiatric disorders, including manic-like behavior and seizures. Valproate treatment may help manage these conditions, unlike lithium.
Area of Science:
- Neuroscience
- Genetics
- Psychiatry
Background:
- SHANK3 gene mutations and duplications are linked to neuropsychiatric disorders.
- SHANK3 dosage is critical for brain function, but overexpression's role was unclear.
- Previous studies were confounded by multiple genes in duplications.
Purpose of the Study:
- To investigate if SHANK3 overexpression causes human disorders.
- To explore the mechanism behind SHANK3-related phenotypes.
- To identify potential therapeutic strategies for SHANK3-associated conditions.
Main Methods:
- Created Shank3 transgenic mice to model human SHANK3 duplication.
- Identified patients with small SHANK3 duplications and hyperkinetic disorders.
- Generated a Shank3 in vivo interactome to study molecular mechanisms.
- Tested the efficacy of valproate and lithium in mouse models.
Main Results:
- Shank3 transgenic mice displayed manic-like behavior and seizures.
- Two patients with the smallest SHANK3 duplications had hyperkinetic disorders.
- Shank3 interacts with the Arp2/3 complex, increasing F-actin levels.
- Valproate, but not lithium, rescued the manic-like behavior in mice.
Conclusions:
- SHANK3 overexpression is a cause of hyperkinetic neuropsychiatric disorders.
- SHANK3 influences synaptic function via F-actin regulation.
- This disorder may have a unique pharmacogenetic profile, responsive to valproate.
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