{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nIQSEC2 encodes a guanine nucleotide exchange factor that is pivotal for synaptic function. Under normal conditions, IQSEC2 is anchored at excitatory postsynaptic sites via interactions with PSD‐95 and NMDA receptors, where increases in intracellular Ca²⁺ lead to calmodulin binding and activation of its SEC7 domain. This in turn catalyzes the exchange of GDP for GTP on ARF6, thereby orchestrating downstream signaling events that regulate AMPA receptor trafficking, dendritic spine morphology, and overall synaptic plasticity. Structural studies further reveal that IQSEC2 activity is tightly controlled by autoinhibitory and Ca²⁺‐dependent allosteric mechanisms, and that variants affecting critical domains (such as the IQ, SEC7, and PH domains) can shift this balance, leading to aberrant ARF6 activation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMutations in IQSEC2 have been linked to a broad spectrum of neurodevelopmental disorders. Initially discovered as a cause of nonsyndromic X‐linked intellectual disability, pathogenic variants—including missense, nonsense, frameshift, and splice‐altering mutations—are now recognized to also underlie epilepsy, autistic behaviors, Rett‐like features, microcephaly, and other neuropsychiatric manifestations in both males (who typically exhibit hemizygous loss of function) and females (in whom escape from X‐inactivation contributes to variable expressivity). Dosage sensitivity, as evidenced by copy number gains and by the differential effects on the longer versus shorter IQSEC2 isoforms, further underscores the gene’s critical role in maintaining proper neuronal signaling and network maturation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "23"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nExperimental models and mechanistic studies have reinforced the connection between IQSEC2 dysfunction and disrupted neuronal network maturation. Mouse models harboring loss‐of‐function or mutation‐specific alleles recapitulate key clinical features—including seizures, cognitive deficits, and autistic behaviors—and reveal abnormal elevations in activated ARF6 levels despite absent or mutant IQSEC2 protein. These findings not only illuminate the molecular underpinnings of IQSEC2‐related disorders but also point to potential therapeutic strategies that might normalize synaptic signaling—offering hope for precision medicine approaches in the future."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "24"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Cheryl Shoubridge, Patrick S Tarpey, Fatima Abidi, et al. 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