Loss-of-function mutations inMECP2cause Rett syndrome (RTT), a severe neurological disorder that mainly affects girls. Mutations inMECP2do occur in males occasionally and typically cause severe encephalopathy and premature lethality. Recently, we identified a missense mutation (c.353G>A, p.Gly118Glu [G118E]), which has never been seen before inMECP2, in a young boy who suffered from progressive motor dysfunction and developmental delay. To determine whether this variant caused the clinical symptoms and study its functional consequences, we established two disease models, including human neurons from patient-derived iPSCs and a knock-in mouse line. G118E mutation partially reduces MeCP2 abundance and its DNA binding, and G118E mice manifest RTT-like symptoms seen in the patient, affirming the pathogenicity of this mutation. Using live-cell and single-molecule imaging, we found that G118E mutation alters MeCP2's chromatin interaction properties in live neurons independently of its effect on protein levels. Here we report the generation and characterization of RTT models of a male hypomorphic variant and reveal new insight into the mechanism by which this pathological mutation affects MeCP2's chromatin dynamics. Our ability to quantify protein dynamics in disease models lays the foundation for harnessing high-resolution single-molecule imaging as the next frontier for developing innovative therapies for RTT and other diseases.

Background: Neurodevelopmental disorders (NDDs) affect approximately 15% of children and adolescents worldwide. This group of disorders is often polygenic with varying risk factors, with many associated genes converging on shared molecular pathways, including chromatin regulation and transcriptional control. Understanding how NDD-associated chromatin regulators and protein complexes orchestrate these regulatory pathways is crucial for elucidating NDD pathogenesis and developing targeted therapeutic strategies. Recently, the TCF20/PHF14 chromatin complex was identified in the mammalian brain, expanding the list of chromatin regulatory remodelers implicated in NDDs. This complex—which includes MeCP2, RAI1, TCF20, PHF14, and HMG20A—plays a vital role in epigenetic and transcriptional regulation. Methods: We review and summarize current research and clinical reports pertaining to the different components of the MeCP2-interacting TCF20/PHF14 complex. We examine the NDDs associated with the TCF20/PHF14 complex, explore the molecular and neuronal functions of its components, and discuss emerging therapeutic strategies targeting this complex to mitigate symptoms, with broader applicability to other NDDs. Results: Mutations in the genes encoding the components of the MeCP2-interacting TCF20/PHF14 complex have been linked to various NDDs, underscoring its critical contribution to brain development and NDD pathogenesis. Conclusions: The MeCP2-interacting TCF20/PHF14 complex and its associated NDDs could serve as a model system to provide insight into the interplay between epigenetic regulation and NDD pathogenesis.