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Background  Considerable clinical heterogeneity has been well documented amongst individuals with autism spectrum disorders (ASD). However, little is known about the biological mechanisms underlying phenotypic diversity. Genetic studies have established a strong causal relationship between ASD and molecular defects in the  SHANK3  gene. Individuals with various defects of  SHANK3  display considerable clinical heterogeneity. Different lines of  Shank3  mutant mice with deletions of different portions of coding exons have been reported recently. Variable synaptic and behavioral phenotypes have been reported in these mice, which makes the interpretations for these data complicated without the full knowledge of the complexity of the  Shank3  transcript structure.    Methods  We systematically examined alternative splicing and isoform-specific expression of  Shank3  across different brain regions and developmental stages by regular RT-PCR, quantitative real time RT-PCR (q-PCR), and western blot. With these techniques, we also investigated the effects of neuronal activity and epigenetic modulation on alternative splicing and isoform-specific expression of  Shank3 . We explored the localization and influence on dendritic spine development of different Shank3 isoforms in cultured hippocampal neurons by cellular imaging.    Results  The  Shank3  gene displayed an extensive array of mRNA and protein isoforms resulting from the combination of multiple intragenic promoters and extensive alternative splicing of coding exons in the mouse brain. The isoform-specific expression and alternative splicing of  Shank3  were brain-region/cell-type specific, developmentally regulated, activity-dependent, and involved epigenetic regulation. Different subcellular distribution and differential effects on dendritic spine morphology were observed for different Shank3 isoforms.    Conclusions  Our results indicate a complex transcriptional regulation of  Shank3  in mouse brains. Our analysis of select  Shank3  isoforms in cultured neurons suggests that different  Shank3  isoforms have distinct functions. Therefore, the different types of  SHANK3  mutations found in patients with ASD and different exonic deletions of  Shank3  in mutant mice are predicted to disrupt selective isoforms and result in distinct dysfunctions at the synapse with possible differential effects on behavior. Our comprehensive data on  Shank3  transcriptional regulation thus provides an essential molecular framework to understand the phenotypic diversity in  SHANK3  causing ASD and  Shank3  mutant mice.

molecular autism

Transcriptional and functional complexity of Shank3 provides a molecular framework to understand the phenotypic heterogeneity of SHANK3 causing autism and Shank3 mutant mice