SHANK proteins: roles at the synapse and in autism spectrum disorder

SH3 and multiple ankyrin repeat domains proteins (SHANKs) are encoded by SHANK1, SHANK2 and SHANK3 genes. The three different SHANK genes can produce multiple protein isoforms that are differentially expressed according to developmental stages, cell types and brain regions.Mutations in SHANK genes are a potential monogenic cause for autism spectrum disorder.Neurobiological studies in animal models indicate a wide array of functions for SHANK proteins, from synaptic scaffolding to regulating spine morphology and neurotransmission.Mutant mice carrying different Shank1, Shank2 or Shank3 mutations have some distinct and shared phenotypes at the molecular and functional level. All mutants seem to have altered molecular composition of excitatory synapses and altered neurotransmission, and often display impaired social interaction and repetitive behaviour.Different mutations within the same SHANKgene may cause distinct synaptic and circuitry defects and thus may be responsible for the different clinical features that are seen in patients.Despite being a neurodevelopmental disorder, some neurobiological alterations in autism spectrum disorder may be reversible in adulthood.Adult restoration of SHANK3 levels or restoration of downstream mediators may be a useful therapeutic approach to alleviate some of the synaptic and behavioural impairments that are associated with SHANK3 mutations.