230: MIDEAS Y654S hyperactivates MiDAC in a dominant neurodevelopmental syndrome

Sirvydis K et al., Nat Commun - 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. Key terms: MIDEAS, MiDAC, HDAC1, neurodevelopmental disorder, Y654S. 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. First author:Sirvydis K Journal:Nat Commun DOI:10.1038/s41467-025-65472-x 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/ Support:Base by Base – Stripe donations: https://donate.stripe.com/7sY4gz71B2sN3RWac5gEg00 Official website https://basebybase.com On PaperCast Base by Base you’ll discover the latest in genomics, functional genomics, structural genomics, and proteomics. Episode link: https://basebybase.com/episodes/mideas-y654s-midac-hyperactivity QC:This episode was checked against the original article PDF and publication metadata for the episode release published on 2025-12-17. QC Scope:- article metadata and core scientific claims from the narration- excludes analogies, intro/outro, and music- transcript coverage: Audited the transcript's presentation of the paper's central mechanism: Y654S in MIDEAS causing MiDAC hyperactivity via disruption of an autoinhibitory loop; structural basis from cryo-EM; enzymatic gain-of-function; downstream gene expression and MAPK pathway implications; clinical phenotype overlap with related syndr- transcript topics: MiDAC/MIDEAS composition and function; Y654S de novo variant and clinical phenotype; Cryo-EM structure showing autoinhibitory loop; HDAC activity assays and gain-of-function; CDK phosphorylation site creation and PTMs; Reciprocal gene expression changes and MAPK signaling QC Summary:- factual score: 10/10- metadata score: 10/10- supported core claims: 6- claims flagged for review: 0- metadata checks passed: 4- metadata issues found: 0 Metadata Audited:- article_doi- article_title- article_journal- license Factual Items Audited:- Two unrelated probands carry de novo MIDEAS p.Tyr654Ser (Y654S) variant with overlapping neurodevelopmental features- Y654S disrupts an autoinhibitory loop over the HDAC1 active site, leading to MiDAC hyperactivity- Y654S creates a CD...