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

TL;DR

A mutation in the MIDEAS gene disrupts a regulatory loop, increasing enzyme activity and causing a developmental disorder with multiple symptoms.

Contribution

Identifies a de novo MIDEAS variant as a cause of a neurodevelopmental syndrome through MiDAC hyperactivity.

Findings

A de novo missense variant in MIDEAS (p.Tyr654Ser) is found in two unrelated individuals with a multisystem disorder.

The variant is located in an auto-inhibitory loop of the MiDAC complex, leading to increased deacetylase activity.

Gene expression changes in patient fibroblasts support the hypothesis of MiDAC hyperactivity.

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.

The MiDAC complex regulates gene expression through histone deacetylation. Here, the authors identify a recurrent MIDEAS mutation that disrupts an auto-inhibitory loop, elevating deacetylase activity and causing a multisystem developmental disorder.

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