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Nat Genet. 2017 Nov;49(11):1642-1646. doi: 10.1038/ng.3956. Epub 2017 Sep 18.

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

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Hubrecht Institute-KNAW and University Medical Center Utrecht, Utrecht, the Netherlands.
Department of Genetics, University Medical Center Utrecht, Utrecht, the Netherlands.
Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands.
North East Thames Regional Genetics Service, Great Ormond Street Hospital, London, UK.
Department of Medical Physiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, the Netherlands.


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.

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