Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome
| العنوان: | Missense substitutions at a conserved 14-3-3 binding site in HDAC4 cause a novel intellectual disability syndrome |
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| المؤلفون: | David A. Stevenson, Karen Stals, Andrea Hanson-Kahn, Sian Ellard, Michael Bruccoleri, Clare E. Beesley, Emma Wakeling, Xiang-Jiao Yang, Matthew Wakeling, Sarah H. Elsea, Philippe M. Campeau, Angela Barnicoat, Meriel McEntagart, Richard Caswell, Charles Shaw-Smith, Mary K. Kukolich |
| المصدر: | Hgg Advances HGG Advances, Vol 2, Iss 1, Pp 100015-(2021) |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | Genetics, gain-of-function, biology, Regulatory site, Histone deacetylase 4, QH426-470, Chromosome 2q37 Deletion Syndrome, HDAC4, Phenotype, Article, Chromatin, Histone, intellectual disability, 14-3-3 binding, biology.protein, Molecular Medicine, Missense mutation, Binding site, Genetics (clinical) |
| الوصف: | Summary 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. Loss-of-function variants in histone deacetylase 4 (HDAC4) have been reported to cause brachydactyly-mental retardation (BDMR) syndrome through haploinsufficiency. This report describes 7 individuals with a phenotype distinct from BDMR, all with missense variants in a conserved 14-3-3 site, which are hypothesized to result in a novel gain-of-function effect in HDAC4. |
| تدمد: | 2666-2477 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b952f799a7eb45fbb729625561bb9b53Test https://pubmed.ncbi.nlm.nih.gov/33537682Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....b952f799a7eb45fbb729625561bb9b53 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 26662477 |
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