Alternative titles; symbols
HGNC Approved Gene Symbol: SHANK1
Cytogenetic location: 19q13.33 Genomic coordinates (GRCh38) : 19:50,659,255-50,719,802 (from NCBI)
Members of the SHANK family, such as SHANK1, are enriched in the postsynaptic density (PSD) of central excitatory synapses. SHANK proteins contain multiple protein interaction domains and function as scaffold proteins for various postsynaptic molecules (summary by Hung et al., 2008).
The somatostatin receptor (SSTR) family is widely expressed in neuronal tissue and modulates synaptic responses by interacting with inhibitory G proteins in presynaptic as well as postsynaptic compartments of neurons. Many neurotransmitter receptors are anchored at their respective specific sites of action by specialized anchoring proteins, which may link receptors to components of the synaptic structure or the cytoskeleton. Using the yeast 2-hybrid system to screen for proteins intracellularly associated with the C terminus of rat Sstr2 (182452), Zitzer et al. (1999) identified a partial human cDNA encoding SSTRIP. They screened human brain cDNA libraries and isolated cDNAs representing several full-length SSTRIP splice variants. The longest predicted form of SSTRIP consists of 2,182 amino acids. This isoform contains 6 N-terminal ankyrin repeats followed by SH3 and PDZ domains, 7 proline-rich regions, and a C-terminal sterile alpha motif (SAM), which has been implicated as a dimerization motif. Another SSTRIP isoform lacked the 6 ankyrin repeats and the SH3 domain. Sequence comparisons suggested that SSTRIP and cortactin (164765)-binding protein (603290), form a family of cytoskeletal-anchoring proteins. Fractionation of rat brain membranes indicated that Sstrip is enriched in the PSD fraction. Northern blot analysis of various human tissues detected 9- and 7.5-kb SSTRIP transcripts in the amygdala, hippocampus, substantia nigra, and thalamus. Only the 7.5-kb transcript was found in organs other than brain, such as heart, skeletal muscle, kidney, and liver. In situ hybridization of rat brain sections revealed a striking overlap in the expression patterns of Sstr2 and Sstrip, including in all layers of the cortex and in the hippocampus. Both proteins are also prominently expressed in the medial habenula. However, in the hippocampus, Sstrip mRNA was detected not only in cell bodies but also in the molecular layer, suggesting that Sstrip mRNA may be transported into neuronal dendrites.
Lim et al. (1999) identified 4 alternative splice sites in rat Shank1 and other Shank family members, some of which result in deletion of specific domains in the Shank protein. The expression of Shank splice variants showed differential regulation in various regions of rat brain during development. Immunoblot analysis of rat brain revealed heterogeneity in size and spatiotemporal expression of the Shank isoforms. Shank1 immunoreactivity was concentrated at excitatory synaptic sites in adult brain, and punctate Shank1 staining was seen in developing rat brains by postnatal day 7. Lim et al. (1999) concluded that alternative splicing of Shank family members may regulate the molecular structure and the spectrum of Shank-interacting proteins in PSDs of adult and developing brain.
Mameza et al. (2013) stated that all SHANK proteins, including SHANK1, have a conserved N-terminal domain prior to the 6 ankyrin repeats. They called this domain the SHANK/PROSAP N-terminal (SPN) domain.
Hartz (2005) mapped the SHANK1 gene to chromosome 19q13.33 based on an alignment of the SHANK1 sequence (GenBank AF163302) with the genomic sequence.
Using overlay assays and coimmunoprecipitation experiments, Zitzer et al. (1999) verified that SSTR2 interacts with SSTRIP.
Naisbitt et al. (1999) determined that the PDZ domain of rat Shank mediates binding to the C terminus of GKAP (605445) and that this interaction is important for the synaptic localization of Shank in neurons. In addition, they showed that the SAM domain is responsible for multimerization of Shank and that the proline-rich region contains a specific binding site for cortactin, an actin crosslinking protein involved in the regulation of the cortical actin cytoskeleton. Naisbitt et al. (1999) hypothesized that Shank may function as a scaffold protein in the PSD and potentially crosslink NMDA receptor (see 138249)/PSD95 (602887) complexes and couple them to regulators of the actin cytoskeleton.
Tu et al. (1999) identified a Homer (see HOMER1; 604798)-binding domain in rat Shank. Shank and Homer coimmunoprecipitated from rat brain and colocalized at PSDs. Shank also clustered mGluR5 (138245) in heterologous cells in the presence of Homer and mediated the coclustering of Homer with PSD95/GKAP. Tu et al. (1999) concluded that Shank may crosslink Homer and PSD95 complexes in the PSD and mediate mGluR and NMDA receptor signaling.
Using rat Homer1b, human HOMER3A (604800), and rat Shank, Hayashi et al. (2009) showed that Homer and Shank formed a mesh-like matrix structure.
Using a human brain expression cDNA library in a yeast 2-hybrid screen, Mameza et al. (2013) found that the isolated SPN domain of human SHANK1 interacted with a fragment of SHANK1 that encompassed the entire ankyrin repeat region. Using rat Shank3 (606230), they showed that this tight intramolecular interaction at the N terminus of Shank3 restricted the availability of the ankyrin repeat region to bind its ligands, Sharpin (611885) and alpha-fodrin (SPTAN1; 182810).
Sato et al. (2012) provided evidence that disruption of the SHANK1 gene may contribute to the development of autism spectrum disorder (see, e.g., ASD, 209850) in males. Microarray analysis of 1,158 unrelated Canadian patients with autism spectrum disorder identified 1 male patient with a heterozygous 63.8-kb deletion eliminating exons 1 to 20 of the SHANK1 gene and the neighboring gene CLEC11A (604713). The mutation was found to segregate with high-functioning autism, including Asperger syndrome (see 608638), in 2 additional males of this family. Two females without autism also carried the deletion, although both women were shy and had anxiety. Whole-exome sequencing of 2 affected males with the deletion identified a truncating mutation (tyr313 to ter) in the PCDHGA11 gene (606298) that segregated with the SHANK1 deletion and may have contributed to the phenotype. In a separate microarray analysis, 1 of 456 European individuals with ASD was found to carry a de novo heterozygous 63.4-kb deletion affecting the last 3 exons of SHANK1 and the entire neighboring SYT3 gene (600327); deletion of SYT3 may have contributed to the phenotype in this patient. This patient had a maternal half-sister with autism who did not carry the deletion. The deletions in the first family and in the second patient did not overlap. No deletions affecting the SHANK1 gene were identified in 15,122 controls individuals. Sato et al. (2012) noted that haploinsufficiency of the SHANK2 (603290) and SHANK3 (606230) genes have been implicated in autism, and suggested that SHANK1 deletions may also contribute to the phenotype in males, with reduced penetrance in female carriers.
Hung et al. (2008) found that Shank1 -/- mice were born at the expected mendelian ratio and were grossly indistinguishable from wildtype, with no abnormalities in size or histologic structure of brain. Shank1 -/- mice showed altered PSD protein composition, reduced size of dendritic spines, smaller and thinner PSDs, and weaker basal synaptic transmission compared with wildtype. Synaptic plasticity appeared normal in Shank1 -/- mice. Adult Shank1 -/- mice exhibited increased anxiety-related behavior and impaired contextual fear memory. Shank1 -/- mice were poor breeders, giving birth only rarely, and Shank1 -/- females did not nurture their pups, resulting in death before weaning. Shank1 -/- mice displayed enhanced spatial learning compared with wildtype, but they were unable to retain the learning enhancement long term. The authors concluded that SHANK1 plays important roles in synapse structure and function and has differential involvement in specific cognitive processes.
Wohr et al. (2011) observed that Shank1-null mice had low levels of ultrasonic vocalizations and scent marks compared to wildtype mice. Shank1-null pups emitted fewer vocalizations when isolated from their mothers and littermates, and adult Shank1-null mice deposited fewer scent marks in proximity to females compared to controls. In addition, wildtype mice changed their calling pattern dependent on previous female interactions, while Shank1-null mice were unaffected, indicating a failure of Shank1-null males to learn from a social experience. Wohr et al. (2011) suggested that these abnormal behaviors were consistent with a phenotype relevant to social communication deficits in autism.
Hartz, P. A. Personal Communication. Baltimore, Md. 1/19/2005.
Hayashi, M. K., Tang, C., Verpelli, C., Narayanan, R., Stearns, M. H., Xu, R.-M., Li, H., Sala, C., Hayashi, Y. The postsynaptic density proteins Homer and Shank form a polymeric network structure. Cell 137: 159-171, 2009. [PubMed: 19345194] [Full Text: https://doi.org/10.1016/j.cell.2009.01.050]
Hung, A. Y., Futai, K., Sala, C., Valtschanoff, J. G., Ryu, J., Woodworth, M. A., Kidd, F. L., Sung, C. C., Miyakawa, T., Bear, M. F., Weinberg, R. J., Sheng, M. Smaller dendritic spines, weaker synaptic transmission, but enhanced spatial learning in mice lacking Shank1. J. Neurosci. 28: 1697-1708, 2008. [PubMed: 18272690] [Full Text: https://doi.org/10.1523/JNEUROSCI.3032-07.2008]
Lim, S., Naisbitt, S., Yoon, J., Hwang, J.-I., Suh, P.-G., Sheng, M., Kim, E. Characterization of the Shank family of synaptic proteins: multiple genes, alternative splicing, and differential expression in brain and development. J. Biol. Chem. 274: 29510-29518, 1999. [PubMed: 10506216] [Full Text: https://doi.org/10.1074/jbc.274.41.29510]
Mameza, M. G., Dvoretskova, E., Bamann, M., Honck, H.-H., Guler, T., Boeckers, T. M., Schoen, M., Verpelli, C., Sala, C., Barsukov, I., Dityatev, A., Kreienkamp, H.-J. SHANK3 gene mutations associated with autism facilitate ligand binding to the Shank3 ankyrin repeat region. J. Biol. Chem. 288: 26697-26708, 2013. [PubMed: 23897824] [Full Text: https://doi.org/10.1074/jbc.M112.424747]
Naisbitt, S., Kim, E., Tu, J. C., Xiao, B., Sala, C., Valtschanoff, J., Weinberg, R. J., Worley, P. F., Sheng, M. Shank, a novel family of postsynaptic density proteins that binds to the NMDA receptor/PSD-95/GKAP complex and cortactin. Neuron 23: 569-582, 1999. [PubMed: 10433268] [Full Text: https://doi.org/10.1016/s0896-6273(00)80809-0]
Sato, D., Lionel, A. C., Leblond, C. S., Prasad, A., Pinto, D., Walker, S., O'Connor, I., Russell, C., Drmic, I. E., Hamdan, F. F., Michaud, J. L., Endris, V., and 19 others. SHANK1 deletions in males with autism spectrum disorder. Am. J. Hum. Genet. 90: 879-887, 2012. [PubMed: 22503632] [Full Text: https://doi.org/10.1016/j.ajhg.2012.03.017]
Tu, J. C., Xiao, B., Naisbitt, S., Yuan, J. P., Petralia, R. S., Brakeman, P., Doan, A., Aakalu, V. K., Lanahan, A. A., Sheng, M., Worley, P. F. Coupling of mGluR/Homer and PSD-95 complexes by the Shank family of postsynaptic density proteins. Neuron 23: 583-892, 1999. [PubMed: 10433269] [Full Text: https://doi.org/10.1016/s0896-6273(00)80810-7]
Wohr, M., Roullet, F. I., Hung, A. Y., Sheng, M., Crawley, J. N. Communication impairments in mice lacking Shank1: reduced levels of ultrasonic vocalizations and scent marking behavior. PLoS One 6: e20631, 2011. Note: Electronic Article. [PubMed: 21695253] [Full Text: https://doi.org/10.1371/journal.pone.0020631]
Zitzer, H., Honck, H.-H., Bachner, D., Richter, D., Kreienkamp, H.-J. Somatostatin receptor interacting protein defines a novel family of multidomain proteins present in human and rodent brain. J. Biol. Chem. 274: 32997-33001, 1999. [PubMed: 10551867] [Full Text: https://doi.org/10.1074/jbc.274.46.32997]