The indispensable role of Mediator complex subunit 27 during neurodevelopment.

BACKGROUND: MED27 is a subunit of the Mediator complex, a highly conserved protein assembly that initiates transcription by bridging transcription factors bound at enhancers to RNA polymerase II transcription machinery at promoters. Recently, we identified an autosomal recessive neurodevelopmental disorder (NDD) caused by loss-of-function (LoF) variants in the MED27 gene. Affected individuals exhibit global developmental delay, intellectual disability, dystonia, and cerebellar atrophy, highlighting the neuronal system's vulnerability to MED27 disruptions. RESULTS: To investigate the pathogenicity mechanisms and essential roles of this gene during neurodevelopment, we generated multiple zebrafish lines with LoF mutations in med27. Homozygous mutant zebrafish displayed severe developmental defects, motor deficits, and cerebellar atrophy, recapitulating the clinical phenotypes observed in MED27-NDD patients. Rescue experiments revealed that patient-specific mutant MED27 mRNA failed to restore normal phenotypes in mutant zebrafish, unlike wildtype MED27 mRNA, underscoring the clinical relevance of our models. Molecular analysis identified transcription factors foxo3a and fosab as direct downstream targets of med27. These genes are well-established master regulators in the central nervous system, providing mechanistic insights into how med27 disruption impairs neuronal and cerebellar development. CONCLUSION: Our findings establish med27 as a critical gene of embryogenesis and neurogenesis, shedding light on the disease mechanism underlying MED27-associated NDDs.