Germline mutations affecting the histone H4 core cause a developmental syndrome by altering DNA damage response and cell cycle control

Federico Tessadori, Jacques C Giltay, Jane A Hurst, Maarten P Massink, Karen Duran, Harmjan R Vos, Robert M van Es, Richard H Scott, Koen L I van Gassen, Jeroen Bakkers, Gijs van Haaften,

Research output: Contribution to journal/periodicalArticleScientificpeer-review

Abstract

Covalent modifications of histones have an established role as chromatin effectors, as they control processes such as DNA replication and transcription, and repair or regulate nucleosomal structure. Loss of modifications on histone N tails, whether due to mutations in genes belonging to histone-modifying complexes or mutations directly affecting the histone tails, causes developmental disorders or has a role in tumorigenesis. More recently, modifications affecting the globular histone core have been uncovered as being crucial for DNA repair, pluripotency and oncogenesis. Here we report monoallelic missense mutations affecting lysine 91 in the histone H4 core (H4K91) in three individuals with a syndrome of growth delay, microcephaly and intellectual disability. Expression of the histone H4 mutants in zebrafish embryos recapitulates the developmental anomalies seen in the patients. We show that the histone H4 alterations cause genomic instability, resulting in increased apoptosis and cell cycle progression anomalies during early development. Mechanistically, our findings indicate an important role for the ubiquitination of H4K91 in genomic stability during embryonic development.

Original languageEnglish
Pages (from-to)1642-1646
Number of pages5
JournalNature Genetics
Volume49
Issue number11
DOIs
Publication statusPublished - Nov 2017

Keywords

  • Adolescent
  • Animals
  • Apoptosis
  • Cell Cycle Checkpoints
  • Child
  • DNA Damage
  • DNA Repair
  • Developmental Disabilities
  • Embryo, Nonmammalian
  • Female
  • Gene Expression Regulation, Developmental
  • Genomic Instability
  • Germ-Line Mutation
  • Histones
  • Humans
  • Infant
  • Intellectual Disability
  • Microcephaly
  • Mutation, Missense
  • Nucleosomes
  • Syndrome
  • Zebrafish
  • Journal Article

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