Mutations of Shank3 in autism and mouse models
Autism represents a spectrum of behavioral and cognitive disorders characterized by deficits in language development, social interactions, and repetitive behaviors. A significant fraction of ASD is caused by de novo or rare mutations, and the Shank3 gene is one of the genes with multiple mutations linked to this disorder. This link is confirmed in GWAS studies. Interestingly, ASD cases with Shank3 mutations are characterized by high variability of phenotypes ranging from severe cases of autistic disorder to milder variants with Asperger syndrome. Recently, a number of groups created different Shank3 knockout mice models attempting to reproduce effects of genetic perturbations discovered in ASD patients. Strategies employed by different groups have demonstrated that levels of Shank3 protein are decreased to different extent by knocking out different exons of the Shank3 gene likely due to transcription from spared intragenic promoters. The phenotypes of Shank3 mutant mice were diverse possibly reflecting variability of ASD symptoms in patients with Shank3 mutations. At the synapse, Shank3 interacts with multiple key players such as Homer, mGluRs, GKAP and cytoskeletal proteins suggesting that mutations of this protein would lead to multiple effects at the synapse involving perturbations in multiple molecular pathways. How different mutations and multiple synaptic pathways can evoke behavioral and cognitive phenotypes of autism remains a central challenge of research, and Shank3 mutations embody a good example of this problem.