Publication Date
10-1-2023
Journal
Genes Development
DOI
10.1101/gad.350733.123
PMID
37890975
PMCID
PMC10691473
PubMedCentral® Posted Date
10-1-2023
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Female, Humans, Male, Mice, Animals, Chromatin, Brain, Methyl-CpG-Binding Protein 2, Rett Syndrome, Mutation, Neurons, : chromatin dynamics, MeCP2, neurological disorders, Rett syndrome, single-molecular imaging
Abstract
Loss-of-function mutations in MECP2 cause Rett syndrome (RTT), a severe neurological disorder that mainly affects girls. Mutations in MECP2 do 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 in MECP2, 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.
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