A de novo missense variant in MIDEAS results in increased deacetylase activity of the MiDAC HDAC complex causing a neurodevelopmental syndrome

Louise Fairall, Kristupas Sirvydis, Robert E. Turnbull, Suzan JG Knottnerus, Oksana Gonchar, Frederick W. Muskett, Rebekah Jukes-Jones, Lonneke van Brussel, Ellen van de Geer, Koen van Gassen, Paul Badenhorst, Diana Johnson, Paulien A. Terhal, Peter M. van Hasselt, Richard H. van Jaarsveld () and John WR Schwabe ()
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Louise Fairall: University of Leicester, Institute for Structural and Chemical Biology, Department of Molecular and Cell Biology
Kristupas Sirvydis: University of Leicester, Institute for Structural and Chemical Biology, Department of Molecular and Cell Biology
Robert E. Turnbull: University of Leicester, Institute for Structural and Chemical Biology, Department of Molecular and Cell Biology
Suzan JG Knottnerus: University Medical Center Utrecht, Department of Genetics
Oksana Gonchar: University of Leicester, Institute for Structural and Chemical Biology, Department of Molecular and Cell Biology
Frederick W. Muskett: University of Leicester, Institute for Structural and Chemical Biology, Department of Molecular and Cell Biology
Rebekah Jukes-Jones: University of Leicester, Institute for Structural and Chemical Biology, Department of Molecular and Cell Biology
Lonneke van Brussel: University Medical Center Utrecht, Department of Genetics
Ellen van de Geer: University Medical Center Utrecht, Department of Genetics
Koen van Gassen: University Medical Center Utrecht, Department of Genetics
Paul Badenhorst: University of Birmingham, Institute of Cancer and Genomic Sciences
Diana Johnson: Sheffield Children’s NHS Foundation Trust, Department of Clinical Genetics
Paulien A. Terhal: University Medical Center Utrecht, Department of Genetics
Peter M. van Hasselt: University Medical Centre Utrecht, Department of Metabolic Disease, Wilhelmina Children’s Hospital
Richard H. van Jaarsveld: University Medical Center Utrecht, Department of Genetics
John WR Schwabe: University of Leicester, Institute for Structural and Chemical Biology, Department of Molecular and Cell Biology

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract MIDEAS is a scaffold protein that, together with DNTTIP1, mediates assembly of the MiDAC histone deacetylase complex. Mice lacking MiDAC die before birth suggesting a key developmental function. Here, we report two unrelated individuals, with a multisystem disorder characterised by delayed speech development, joint contractures, dysmorphic features and dysmotility of the gut. Both individuals have the same de novo heterozygous missense variant in MIDEAS (p.Tyr654Ser). A cryoEM structure of the MiDAC complex reveals that this amino acid is located in a conserved auto-inhibitory loop that covers the active site of the deacetylase enzyme. We suggest that the variant results in loop displacement leading to elevated deacetylase activity. In support, we observe reciprocal gene expression changes in patient fibroblasts compared with a cell line following rapid MiDAC degradation. Our results establish MIDEAS as a dominant monogenic disease gene and that hyperactivity of the MiDAC complex results in a characteristic multisystem disorder.

Date: 2025
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DOI: 10.1038/s41467-025-65472-x

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