SHANK2 is located on the 11q13.3 region of chromosome 11 and is composed of 25 exons.
SHANK2 mutations leading to ASD can arise either de novo or be inherited from the parents. Mutations in SHANK2 include: CNV (deletions) and loss of Function (LoF) variants. SHANK2 mutations are not always fully penetrant and additional unknown genetic/epigenetic/environmental factors might explain the difference in clinical trajectory of the patients.
SHANK2 codes for a scaffolding protein expressed at the synapses of excitatory neurons in different brain areas: cortex, hippocampus, cerebellum, olfactif bulbs, thalamus. SHANK2 protein is also expressed in peripheral organs such as liver, kidney, lung and pancreas.
Regulation of the SHANK2 expression involves miRNA.
SHANK2 protein comprises 5 protein domains allowing the interaction of a wide number of synaptic proteins like receptors as well as actin cytoskeleton and signaling proteins. Abnormalities in SHANK2 functions may alter synaptic communications between neurons in regions underlying cognitive functions. In particular, SHANK2 mutations lead to a reduction of the synapses number along the dendrite. A study using iPSC-derived neurons from patients showed that SHANK2 mutations can also lead to hyper connectivity of cortical neurons.