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Inherited and de novo SHANK2 variants associated with autism spectrum disorder impair neuronal morphogenesis and physiology

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Mutations in the postsynaptic scaffolding gene SHANK2 have recently been identified in individuals with autism spectrum disorder (ASD) and intellectual disability. However, the cellular and physiological consequences of these mutations in neurons remain unknown. We have analyzed the functional impac...

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Bibliographic Details
Main Authors: Berkel, Simone (Author) , Gass, Peter (Author) , Schratt, Gerhard (Author) , Rappold, Gudrun (Author)
Format: Article (Journal)
Language:English
Published: 15 January 2012
In: Human molecular genetics
Year: 2012, Volume: 21, Issue: 2, Pages: 344-357
ISSN:1460-2083
DOI:10.1093/hmg/ddr470
Online Access:Verlag, teilw. kostenfrei, Volltext: http://dx.doi.org/10.1093/hmg/ddr470
Verlag, teilw. kostenfrei, Volltext: https://academic-oup-com.ezproxy.medma.uni-heidelberg.de/hmg/article/21/2/344/663222
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Author Notes:Simone Berkel, Wannan Tang, Mario Treviño, Miriam Vogt, Horst Andreas Obenhaus, Peter Gass, Stephen Wayne Scherer, Rolf Sprengel, Gerhard Schratt and Gudrun Anna Rappold
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Summary:Mutations in the postsynaptic scaffolding gene SHANK2 have recently been identified in individuals with autism spectrum disorder (ASD) and intellectual disability. However, the cellular and physiological consequences of these mutations in neurons remain unknown. We have analyzed the functional impact caused by two inherited and one de novo SHANK2 mutations from ASD individuals (L1008_P1009dup, T1127M, R462X). Although all three variants affect spine volume and have smaller SHANK2 cluster sizes, T1127M additionally fails to rescue spine volume in Shank2 knock-down neurons. R462X is not able to rescue spine volume and dendritic branching and lacks postsynaptic clustering, indicating the most severe dysfunction. To demonstrate that R462X when expressed in mouse can be linked to physiological effects, we analyzed synaptic transmission and behavior. Principal neurons of mice expressing rAAV-transduced SHANK2-R462X present a specific, long-lasting reduction in miniature postsynaptic AMPA receptor currents. This dominant negative effect translates into dose-dependent altered cognitive behavior of SHANK2-R462X-expressing mice, with an impact on the penetrance of ASD.
Item Description:Gesehen am 04.04.2018
Physical Description:Online Resource
ISSN:1460-2083
DOI:10.1093/hmg/ddr470

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