Show Notes
️Episode 230: MIDEAS Y654S hyperactivates MiDAC in a dominant neurodevelopmental syndrome
In this episode of PaperCast Base by Base, we explore A recurrent de novo MIDEAS p.Tyr654Ser variant disrupts an autoinhibitory loop in the MiDAC complex, increasing HDAC1 deacetylase activity and causing a multisystem neurodevelopmental disorder
Study Highlights:
Two unrelated probands carry the same de novo heterozygous MIDEAS p.Tyr654Ser variant and present with speech delay, progressive joint contractures, facial dysmorphism and gastrointestinal dysmotility. A 2.9 Å cryo-EM structure shows Y654 lies in a conserved loop of MIDEAS that covers the HDAC1 active site and positions I659 into the active site channel. The Y654S change creates an STP CDK consensus site that is highly phosphorylated and leads to displacement of the inhibitory loop, producing a 3–5-fold increase in MiDAC deacetylase activity in vitro. Patient fibroblast transcriptomes display largely reciprocal gene expression changes compared with MiDAC-depleted cells, and MiDAC loss upregulates MAP2K6 and MAP2K3 implicating p38 MAPK pathway involvement.
Conclusion:
MIDEAS p.Tyr654Ser is a dominant monogenic cause of a neurodevelopmental syndrome driven by hyperactivity of the MiDAC HDAC complex
Music:
Enjoy the music based on this article at the end of the episode.
Reference:
Sirvydis K., Fairall L., Knottnerus SJG., Gonchar O., Muskett FW., Jukes-Jones R., van Brussel L., van de Geer E., van Gassen K., Badenhorst P., van Hasselt PM., van Jaarsveld RH., Schwabe J.W.R., et al. A de novo missense variant in MIDEAS results in increased deacetylase activity of the MiDAC HDAC complex causing a neurodevelopmental syndrome. Nat Commun. 2025;16:10472. https://doi.org/10.1038/s41467-025-65472-x
License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/
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