De novo mutations in the MiDAC HDAC complex cause a neurodevelopmental 2 syndrome resulting from increased deacetylase activity [qPRO-seq]

ABSTRACT: MIDEAS is a scaffold protein that, together with DNTTIP1, mediates assembly of the 36 MiDAC histone deacetylase complex. Mice lacking MiDAC die before birth suggesting 37 a key developmental function. Here, we report two unrelated individuals, with a 38 multisystem disorder characterized by delayed speech development, joint 39 contractures, dysmorphic features and dysmotility of the gut. Both individuals have the 40 same de novo heterozygous mis-sense variant in MIDEAS (Tyr654Ser). A cryoEM 41 structure of the MiDAC complex reveals that this amino acid is located in a conserved 42 auto-inhibitory loop that covers the active site of the deacetylase enzyme. We suggest 43 that the mutation results in loop displacement leading to elevated deacetylase activity. 44 In support, we observe reciprocal gene expression changes in patient fibroblasts 45 compared with a cell line following rapid MiDAC degradation. Our results establish 46 Mideas as a novel dominant monogenic disease gene and that hyperactivity of the 47 MiDAC complex results in a characteristic multisystem disorder.

ORGANISM(S): Homo sapiens

PROVIDER: GSE297958 | GEO | 2025/10/13

REPOSITORIES: GEO