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

Tessadori, F. et al. (2017) Germline mutations affecting the histone H4 core cause a developmental syndrome by altering DNA damage response and cell cycle control. Nature Genetics, 49(11), pp. 1642-1646. (doi:10.1038/ng.3956) (PMID:28920961)

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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 structure1,2. 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 disorders3,4,5,6 or has a role in tumorigenesis7,8. More recently, modifications affecting the globular histone core have been uncovered as being crucial for DNA repair, pluripotency and oncogenesis9,10. 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.

Item Type:Articles
Additional Information:We acknowledge support from the Netherlands Cardiovascular Research Initiative, Dutch Heart Foundation grant CVON2014-18 CONCOR-GENES and the ‘Proteins at Work’ program of the Netherlands Organization for Scientific Research (NWO; project 184.032.201). The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant HICF-1009-003), a parallel funding partnership between the Wellcome Trust with the Department of Health and the Wellcome Trust Sanger Institute (grant WT098051). The views expressed in this publication are those of the author(s) and not necessarily those of the Wellcome Trust or the Department of Health. The study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12, granted by the Republic of Ireland REC). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Tobias, Professor Edward
Authors: Tessadori, F., Giltay, J. C., Hurst, J. A., Massink, M. P., Duran, K., Vos, H. R., Deciphering Developmental Disorders Study, , van Es, R. M., Scott, R. H., van Gassen, K. L.I., Bakkers, J., and van Haaften, G.
College/School:College of Medical Veterinary and Life Sciences > School of Medicine, Dentistry & Nursing
Journal Name:Nature Genetics
Publisher:Nature Research
ISSN:1061-4036
ISSN (Online):1546-1718

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