摘要：SummaryMECP2 loss-of-function mutations cause Rett syndrome, a neurodevelopmental disorder resulting from a disrupted brain transcriptome. How these transcriptional defects are decoded into a disease proteome remains unknown. We studied the proteome of Rett cerebrospinal fluid (CSF) to identify consensus Rett proteome and ontologies shared across three species. Rett CSF proteomes enriched proteins annotated to HDL lipoproteins, complement, mitochondria, citrate/pyruvate metabolism, synapse compartments, and the neurosecretory protein VGF. We used shared Rett ontologies to select analytes for orthogonal quantification and functional validation. VGF and ontologically selected CSF proteins had genotypic discriminatory capacity as determined by receiver operating characteristic analysis inMecp2-/yandMecp2−/+.Differentially expressed CSF proteins distinguished Rett from a related neurodevelopmental disorder, CDKL5 deficiency disorder. We propose thatMecp2mutant CSF proteomes and ontologies inform putative mechanisms and biomarkers of disease. We suggest that Rett syndrome results from synapse and metabolism dysfunction.Graphical abstractDisplay OmittedHighlights•Shared Rett CSF proteome ontologies across species and experimental approaches•Rett CSF proteome enriches HDL lipoprotein, mitochondria, and synapse ontologies•VGF levels discriminateMecp2-/y,Mecp2−/+, from control CSF•Rett CSF proteome and ontologies are distinct from those inCdkl5-/yCSFDisease; Pathophysiology; Clinical neuroscience; Proteomics
