SHANK3 is a leading autism candidate gene, with mutations occurring in between 1 and 2 percent of individuals with autism spectrum disorders. SHANK3 encodes a protein that is essential for proper functioning of the synapse, the junction between neurons.

Relevance to autism:

Both spontaneous and inherited SHANK3 mutations inhibit the role of the protein, which forms a scaffolding to organize other proteins at the synapse. Among other functions, it secures a receptor for a chemical messenger called glutamate to the receiving end of the synapse. Glutamate signaling is needed to establish learning and memory. Imbalances in glutamate signaling have been implicated in autism.

SHANK3 is located in the 22q13 chromosomal region, which is deleted in individuals with Phelan-McDermid syndrome, a disorder characterized by severe intellectual disability and delayed speech, often accompanied by autism.

A study published June 2013 in Molecular Autism found that the majority of people lacking a functional copy of the SHANK3 gene have both autism and severe intellectual disability1.

Researchers first linked the gene to autism in 2007, when they found several children with autism who carry SHANK3 mutations2. Several studies since then have found SHANK3 mutations in people with the disorder3,4,5. The mutations described so far range from deletions of the entire gene to subtle changes that substitute individual amino acids.

Since late 2010, no fewer than five different lines of SHANK3 mutant mice have been established, with different parts of the protein disrupted in the various models6. This substantial effort reflects in part SHANK3’s importance in the brain, and in part its complex structure. Each mouse model exhibits different autism-like features, ranging from abnormal social interactions to obsessive self-grooming.

  1. Soorya L. et al. Mol. Autism 4, 18 (2013) PubMed
  2. Durand C.M. et al. Nat. Genet. 39, 25-27 (2007) PubMed
  3. Gauthier J. et al. Am. J. Med. Genet. B. Neuropsychiatr. Genet. 150B, 421-424 (2009) PubMed
  4. Moessner R. et al. Am. J. Hum. Genet. 81, 1289-1297 (2007) PubMed
  5. Boccuto L. et al. Eur. J. Hum. Genet. Epub ahead of print (2012) PubMed
  6. Bozdagi O. et al. Mol. Autism Epub ahead of print (2010) PubMed