{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSHANK3 encodes a multidomain postsynaptic scaffold protein that is central to establishing and maintaining excitatory synapses. It orchestrates the formation and maturation of dendritic spines by physically linking glutamate receptors to the actin cytoskeleton and interacting with key partners such as neuroligins. In doing so, SHANK3 coordinates trans‐synaptic signals that regulate receptor trafficking, ion‐channel function, and actin polymerization—processes essential for proper synaptic transmission and plasticity. Notably, its N‐terminal SPN domain binds active small GTPases, further influencing receptor surface expression and channel activity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGenetic studies have established that proper SHANK3 dosage is critical for normal brain function. Both loss‐of‐function mutations (including intragenic deletions, splice‐site disruptions, and missense variants) and gene duplications have been implicated in a range of neurodevelopmental and neuropsychiatric conditions—including autism spectrum disorder, Phelan–McDermid syndrome, schizophrenia, and intellectual disability. These mutations and copy‐number variations disrupt normal synaptic architecture and disturb the balance of excitatory/inhibitory transmission through mechanisms such as impaired dendritic spine development, abnormal receptor signaling and altered epigenetic regulation. Comprehensive clinical–genetic analyses, including studies of deletion breakpoints and transcript isoform variations, further support genotype–phenotype correlations that refine our understanding of SHANK3–associated syndromes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "31"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its classical role at central nervous system synapses, SHANK3 is emerging as a multifunctional protein with influence in peripheral as well as developmental processes. Its regulatory repertoire now encompasses modulation of integrin activation and actin dynamics via direct binding to small GTPases, as well as control of protein turnover through deubiquitinating enzymes like USP8. Such mechanisms contribute not only to proper synaptic function but also to peripheral neuronal processes including pain perception in sensory neurons and neuromuscular junction stability in skeletal muscle. Recent studies employing human telencephalic organoids further suggest that SHANK3’s dosage impacts early brain development, thereby broadening the pathogenic landscape of SHANK3 mutations."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "32", "end_ref": "36"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Christelle M Durand, Catalina Betancur, Tobias M Boeckers, et al. 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