SH3 and multiple ankyrin repeat domains 3 (Shank3), also known as proline-rich synapse-associated protein 2 (ProSAP2), is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

that in humans is encoded by the ''SHANK3''

gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...

chromosome 22 Chromosome 22 is one of the 23 pairs of chromosomes in human cells. Humans normally have two copies of chromosome 22 in each cell. Chromosome 22 is the second smallest human chromosome, spanning about 51 million DNA base pairs and representing b ...

. Additional isoforms have been described for this gene but they have not yet been experimentally verified.

Function

This gene is one of the 3-member Shank gene family (Shank1-3). The gene encodes a protein that contains 5 interaction domains or motifs including the ankyrin repeats domain (ANK), a src 3 domain ( SH3), a proline-rich domain, a PDZ domain and a sterile α motif domain (SAM). Shank proteins are multidomain scaffold proteins of the postsynaptic density that connect

neurotransmitter A neurotransmitter is a signaling molecule secreted by a neuron to affect another cell across a Chemical synapse, synapse. The cell receiving the signal, or target cell, may be another neuron, but could also be a gland or muscle cell. Neurotra ...

receptors, ion channels, and other membrane proteins to the actin cytoskeleton and G-protein-coupled signaling pathways. Shank proteins also play a role in

synapse In the nervous system, a synapse is a structure that allows a neuron (or nerve cell) to pass an electrical or chemical signal to another neuron or a target effector cell. Synapses can be classified as either chemical or electrical, depending o ...

formation and

dendritic spine A dendritic spine (or spine) is a small membrane protrusion from a neuron's dendrite that typically receives input from a single axon at the synapse. Dendritic spines serve as a storage site for synaptic strength and help transmit electrical sign ...

maturation.

Clinical significance

Mutations in this gene are associated with

autism spectrum disorder Autism, also known as autism spectrum disorder (ASD), is a neurodevelopmental disorder characterized by differences or difficulties in social communication and interaction, a preference for predictability and routine, sensory processing di ...

. This gene is often missing in patients with 22q13.3 deletion syndrome (''Phelan–McDermid syndrome''), although not in all cases.

Interactions

SHANK3 has been shown to

interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization advocating for the legal and human rights of children with intersex traits. The organization was founded in 2006 and fo ...

with

ARHGEF7 Rho guanine nucleotide exchange factor 7 is a protein that in humans is encoded by the ''ARHGEF7'' gene. ARHGEF7 is commonly known as the p21-activated protein kinase exchange factor beta (beta-PIX or βPIX), because it was identified by binding ...

Mouse models

Mouse models of SHANK3 include N-terminal knock-outs and a PDZ domain knock-out all of which also show social interaction deficits and variable other phenotypes. Most of these mice are homozygous knock-outs whereas all the human SHANK3 mutations have been heterozygous. In an inducible knockout, restoration of SHANK3 expression in adult mice promoted dendritic spine growth and recovered normal grooming behaviour and voluntary social interaction. However, the reduced locomotion, anxiety and rotarod deficits remained. Germline restoration of the gene's expression rescued all measured phenotypes. Experiments on different developmental windows suggested that early intervention was more effective in restoring behavioural traits.

Rat models

A rat model of SHANK3 was developed using

zinc finger nuclease Zinc-finger nucleases (ZFNs) are artificial restriction enzymes generated by fusing a zinc finger DNA-binding domain to a nuclease, DNA-cleavage domain. Zinc finger domains can be engineered to target specific desired DNA sequences and this enab ...

s targeting exon 6 of the ankyrin (ANK) repeat domain. The deletion (-68bp) resulted in reduction of the full length SHANK3a protein. It is unclear if the expression of other isoforms (b and c) of SHANK3 is affected in this rodent model. The shank3 mutant rats have deficits in long-term social recognition memory but not short-term social recognition memory as well as deficits in attention. These are symptons of impaired

synaptic plasticity In neuroscience, synaptic plasticity is the ability of synapses to Chemical synapse#Synaptic strength, strengthen or weaken over time, in response to increases or decreases in their activity. Since memory, memories are postulated to be represent ...

. In humans, 5 patients have been described harboring varying mutations in exon 6 of the SHANK3 protein.

References

External links

GeneReviews/NCBI/NIH/UW entry on Phelan-McDermid or 22q13.3 deletion syndrome
{{PDB Gallery, geneid=85358 Genes