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

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.

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Journal
Nature Communications
Published
2025-11-25
DOI
https://doi.org/10.1038/s41467-025-65472-x
Primary Topic
Genomics and Rare Diseases
Type
article
Field-Weighted Citation Impact
0.00

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article

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

Pauline Terhal, Paul Badenhorst, Suzan J. G. Knottnerus, Kristupas Sirvydis et al.
Nature Communications
Genomics and Rare Diseases
article

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

Pauline Terhal, Paul Badenhorst, Suzan J. G. Knottnerus, Kristupas Sirvydis, Robert E. Turnbull, Ellen van de Geer, Koen L.I. van Gassen, Frederick W. Muskett, Rebekah Jukes‐Jones, Peter M. van Hasselt, Louise Fairall, Oksana Gonchar, John W. R. Schwabe, Richard H. van Jaarsveld, Diana Johnson, Lonneke van Brussel
article en

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.

Nature CommunicationsVol. 16(1)
University of Leicester (GB), University Medical Center Utrecht (NL), Sheffield Children's NHS Foundation Trust (GB), Wilhelmina Children's Hospital (NL), University of Birmingham (GB)
Wellcome Trust, University of Leicester, Universitair Medisch Centrum Utrecht
Openalex Percentile: Top 62%
Genomics and Rare Diseases
DOIOpen Access PDFOpenAlex
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