6cpk

Structural highlights

Disease

SHAN3_HUMAN Autism;Monosomy 22q13;Schizophrenia. A chromosomal aberration involving SHANK3 is found in patients with chromosome 22q13.3 deletion syndrome. Translocation t(12;22)(q24.1;q13.3) with APPL2/DIP13B.^[1] Defects in SHANK3 are associated with neuropsychiatric disorders such as autism spectrum disorders (ASD), bipolar affective disorders and early dementia onset. ASD are characterized by impairments in reciprocal social interaction and communication as well as restricted and stereotyped patterns of interest and activities. ASD include forms with moderate to severe cognitive impairment and milder forms with higher cognitive ability (Asperger syndrome). Gene duplication is associated with hyperkinetic neuropsychiatric disorders (PubMed:24153177) such as hyperactivity, auditory overstimulation, epilepsy and bipolar affective disorders, among others.^[2] The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry.

Function

SHAN3_HUMAN Major scaffold postsynaptic density protein which interacts with multiple proteins and complexes to orchestrate the dendritic spine and synapse formation, maturation and maintenance. Interconnects receptors of the postsynaptic membrane including NMDA-type and metabotropic glutamate receptors via complexes with GKAP/PSD-95 and HOMER, respectively, and the actin-based cytoskeleton. Plays a role in the structural and functional organization of the dendritic spine and synaptic junction through the interaction with Arp2/3 and WAVE1 complex as well as the promotion of the F-actin clusters. By way of this control of actin dynamics, participates in the regulation of developing neurons growth cone motility and the NMDA receptor-signaling. Also modulates GRIA1 exocytosis and GRM5/MGLUR5 expression and signaling to control the AMPA and metabotropic glutamate receptor-mediated synaptic transmission and plasticity. May be required at an early stage of synapse formation and be inhibited by IGF1 to promote synapse maturation.^[3]

References

1. ↑ Bonaglia MC, Giorda R, Borgatti R, Felisari G, Gagliardi C, Selicorni A, Zuffardi O. Disruption of the ProSAP2 gene in a t(12;22)(q24.1;q13.3) is associated with the 22q13.3 deletion syndrome. Am J Hum Genet. 2001 Aug;69(2):261-8. doi: 10.1086/321293. Epub 2001 Jun 18. PMID:11431708 doi:http://dx.doi.org/10.1086/321293
2. ↑ Han K, Holder JL Jr, Schaaf CP, Lu H, Chen H, Kang H, Tang J, Wu Z, Hao S, Cheung SW, Yu P, Sun H, Breman AM, Patel A, Lu HC, Zoghbi HY. SHANK3 overexpression causes manic-like behaviour with unique pharmacogenetic properties. Nature. 2013 Nov 7;503(7474):72-7. doi: 10.1038/nature12630. Epub 2013 Oct 23. PMID:24153177 doi:http://dx.doi.org/10.1038/nature12630
3. ↑ Shcheglovitov A, Shcheglovitova O, Yazawa M, Portmann T, Shu R, Sebastiano V, Krawisz A, Froehlich W, Bernstein JA, Hallmayer JF, Dolmetsch RE. SHANK3 and IGF1 restore synaptic deficits in neurons from 22q13 deletion syndrome patients. Nature. 2013 Nov 14;503(7475):267-71. doi: 10.1038/nature12618. Epub 2013 Oct 16. PMID:24132240 doi:http://dx.doi.org/10.1038/nature12618