2. Academic Validation
  3. Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome

Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome

  • HGG Adv. 2021 Jan 14;2(1):100015. doi: 10.1016/j.xhgg.2020.100015.
Emma Wakeling 1,  Meriel McEntagart 2,  Michael Bruccoleri 3 4,  Charles Shaw-Smith 5,  Karen L Stals 6,  Matthew Wakeling 7,  Angela Barnicoat 1,  Clare Beesley 8,  DDD Study,  Andrea K Hanson-Kahn 9 10,  Mary Kukolich 11,  David A Stevenson 10,  Philippe M Campeau 12,  Sian Ellard 6,  Sarah H Elsea 13,  Xiang-Jiao Yang 3 4 14,  Richard C Caswell 6 7
Affiliations

Affiliations

  • 1 North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street, London WC1N 3JH, UK.
  • 2 Medical Genetics, Floor 0 Jenner Wing, St George's University Hospitals NHS Foundation Trust, Cranmer Terrace, London SW17 0RE, UK.
  • 3 Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montreal, Quebec, QC H3A 1A3, Canada.
  • 4 Department of Medicine, McGill University Health Center, Montreal, Quebec, QC H3A 1A3, Canada.
  • 5 Department of Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter EX1 2ED, UK.
  • 6 Exeter Genomics Laboratory, Royal Devon and Exeter NHS Foundation Trust, Exeter EX2 5DW, UK.
  • 7 Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter EX2 5DW, UK.
  • 8 Rare & Inherited Disease Laboratory, North Thames Genomic Laboratory Hub, Great Ormond Street Hospital for Children NHS Foundation Trust, 37 Queen Square, London WC1N 3BH, UK.
  • 9 Department of Genetics, Stanford University School of Medicine, 300 Pasteur Drive, H315, Stanford, CA 94305-5208, USA.
  • 10 Department of Pediatrics, Division of Medical Genetics, Stanford University, 300 Pasteur Drive, H315, Stanford, CA 94305-5208, USA.
  • 11 Clinical Genetics, Cook Children's Medical Center, Fort Worth, TX 76104, USA.
  • 12 Department of Pediatrics, CHU Sainte-Justine Hospital, University of Montreal, Montreal, Quebec, QC H3T 1C4, Canada.
  • 13 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • 14 Department of Biochemistry, McGill University Health Center, Montreal, Quebec, QC, Canada.
PMID: 33537682 DOI: 10.1016/j.xhgg.2020.100015
Abstract

Histone deacetylases play crucial roles in the regulation of chromatin structure and gene expression in the eukaryotic cell, and disruption of their activity causes a wide range of developmental disorders in humans. Loss-of-function alleles of HDAC4, a founding member of the class IIa deacetylases, have been reported in brachydactyly-mental retardation syndrome (BDMR). However, while disruption of HDAC4 activity and deregulation of its downstream targets may contribute to the BDMR phenotype, loss of HDAC4 function usually occurs as part of larger deletions of chromosome 2q37; BDMR is also known as chromosome 2q37 deletion syndrome, and the precise role of HDAC4 within the phenotype remains uncertain. Thus, identification of missense variants should shed new light on the role of HDAC4 in normal development. Here, we report seven unrelated individuals with a phenotype distinct from that of BDMR, all of whom have heterozygous de novo missense variants that affect a major regulatory site of HDAC4, required for signal-dependent 14-3-3 binding and nucleocytoplasmic shuttling. Two individuals possess variants altering Thr244 or Glu247, whereas the remaining five all carry variants altering Pro248, a key residue for 14-3-3 binding. We propose that the variants in all seven individuals impair 14-3-3 binding (as confirmed for the first two variants by immunoprecipitation assays), thereby identifying deregulation of HDAC4 as a pathological mechanism in a previously uncharacterized developmental disorder.

Keywords

14-3-3 binding; Histone deacetylase 4; gain-of-function; intellectual disability.

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