{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSHANK1 encodes a postsynaptic scaffolding protein that is critical for the formation and regulation of neuronal synapses. Disruptions in SHANK1, including microdeletions and missense or truncating mutations, have been associated with neurodevelopmental disorders such as autism spectrum disorder (ASD) and schizophrenia. For example, hemizygous SHANK1 deletions segregate with ASD in families—particularly affecting males—while specific promoter variants have been linked to working memory deficits in schizophrenia."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Animal models have further substantiated these findings: Shank1 knockout mice exhibit behavioral phenotypes relevant to the core symptoms of ASD and alterations in synaptic morphology that parallel observations in human patients."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the molecular level, SHANK1 plays a significant role in the regulation of local protein synthesis in dendrites. Its mRNA is not only subject to sophisticated transport mechanisms along microtubules via kinesin motor complexes and RNA-binding proteins but is also tightly controlled at the translational level through complex 5′ untranslated regions containing upstream open reading frames and non-canonical initiation sites. Moreover, SHANK1 mRNA is a target of fragile X mental retardation protein (FMRP), with G-quadruplex structures in its 3′UTR mediating high-affinity FMRP binding—a mechanism that may influence synaptic plasticity and contribute to the pathophysiology seen in fragile X syndrome."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its classical postsynaptic roles, SHANK1 has been implicated in other cellular processes. Beyond the neuronal context, SHANK1 participates in the modulation of integrin activation by sequestering active Rap1 and R-Ras through conserved domains shared with other SHANK family members, thereby influencing cell migration, spreading, and invasion."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Furthermore, aberrant overexpression of SHANK1 in colon cancer tissues has been linked to enhanced cell survival and proliferation via the AKT/mTOR signaling pathway, suggesting that SHANK1 may also function as an oncogene in non-neuronal tissues."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nLastly, while common SHANK1 polymorphisms alone do not appear to confer increased risk for ASD in certain populations, interaction analyses among SHANK family genes indicate that synergistic effects may modulate disease susceptibility."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " Significantly, an ASD-specific recurrent missense mutation in SHANK1 has been shown to disrupt postsynaptic signaling, including the downregulation of mGluR1-IP3R1-mediated calcium release and impairments in synaptic plasticity, directly linking SHANK1 dysfunction to the core symptoms of ASD."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Daisuke Sato, Anath C Lionel, Claire S Leblond, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SHANK1 Deletions in Males with Autism Spectrum Disorder."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Hum Genet (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.ajhg.2012.03.017"}], "href": "https://doi.org/10.1016/j.ajhg.2012.03.017"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "22503632"}], "href": "https://pubmed.ncbi.nlm.nih.gov/22503632"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Leonhard Lennertz, Michael Wagner, Wolfgang Wölwer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A promoter variant of SHANK1 affects auditory working memory in schizophrenia patients and in subjects clinically at risk for psychosis."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Eur Arch Psychiatry Clin Neurosci (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s00406-011-0233-3"}], "href": "https://doi.org/10.1007/s00406-011-0233-3"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21901269"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21901269"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "A Özge Sungur, Rainer K W Schwarting, Markus Wöhr "}, {"type": "b", "children": [{"type": "t", "text": "Behavioral phenotypes and neurobiological mechanisms in the Shank1 mouse model for autism spectrum disorder: A translational perspective."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Behav Brain Res (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.bbr.2017.09.038"}], "href": "https://doi.org/10.1016/j.bbr.2017.09.038"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28963042"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28963042"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Halie J May, Jaehoon Jeong, Anya Revah-Politi, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Truncating variants in the SHANK1 gene are associated with a spectrum of neurodevelopmental disorders."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Genet Med (2021)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41436-021-01222-w"}], "href": "https://doi.org/10.1038/s41436-021-01222-w"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "34113010"}], "href": "https://pubmed.ncbi.nlm.nih.gov/34113010"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Katrin Falley, Janin Schütt, Peter Iglauer, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Shank1 mRNA: dendritic transport by kinesin and translational control by the 5'untranslated region."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Traffic (2009)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1600-0854.2009.00912.x"}], "href": "https://doi.org/10.1111/j.1600-0854.2009.00912.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "19416473"}], "href": "https://pubmed.ncbi.nlm.nih.gov/19416473"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Katrin Studtmann, Janin Olschläger-Schütt, Friedrich Buck, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A non-canonical initiation site is required for efficient translation of the dendritically localized Shank1 mRNA."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0088518"}], "href": "https://doi.org/10.1371/journal.pone.0088518"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24533096"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24533096"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Yang Zhang, Christian M Gaetano, Kathryn R Williams, et al. "}, {"type": "b", "children": [{"type": "t", "text": "FMRP interacts with G-quadruplex structures in the 3'-UTR of its dendritic target Shank1 mRNA."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "RNA Biol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/15476286.2014.996464"}], "href": "https://doi.org/10.1080/15476286.2014.996464"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "25692235"}], "href": "https://pubmed.ncbi.nlm.nih.gov/25692235"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Johanna Lilja, Thomas Zacharchenko, Maria Georgiadou, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SHANK proteins limit integrin activation by directly interacting with Rap1 and R-Ras."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Cell Biol (2017)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/ncb3487"}], "href": "https://doi.org/10.1038/ncb3487"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "28263956"}], "href": "https://pubmed.ncbi.nlm.nih.gov/28263956"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Yujiao Fu, Du Liu, Jialing Guo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Dynamic Change of Shanks Gene mRNA Expression and DNA Methylation in Epileptic Rat Model and Human Patients."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Neurobiol (2020)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1007/s12035-020-01968-5"}], "href": "https://doi.org/10.1007/s12035-020-01968-5"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "32564287"}], "href": "https://pubmed.ncbi.nlm.nih.gov/32564287"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Shuang Qiu, Yan Li, Ye Bai, et al. "}, {"type": "b", "children": [{"type": "t", "text": "SHANK1 polymorphisms and SNP-SNP interactions among SHANK family: A possible cue for recognition to autism spectrum disorder in infant age."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Autism Res (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/aur.2065"}], "href": "https://doi.org/10.1002/aur.2065"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30629339"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30629339"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Yue Qin, Yasong Du, Liqiang Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A recurrent SHANK1 mutation implicated in autism spectrum disorder causes autistic-like core behaviors in mice via downregulation of mGluR1-IP3R1-calcium signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Psychiatry (2022)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41380-022-01539-1"}], "href": "https://doi.org/10.1038/s41380-022-01539-1"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "35388181"}], "href": "https://pubmed.ncbi.nlm.nih.gov/35388181"}]}]}]}