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

TY - JOUR

T1 - Germline mutations affecting the histone H4 core cause a developmental syndrome by altering DNA damage response and cell cycle control

AU - Tessadori, Federico

AU - Giltay, Jacques C

AU - Hurst, Jane A

AU - Massink, Maarten P

AU - Duran, Karen

AU - Vos, Harmjan R

AU - van Es, Robert M

AU - Scott, Richard H

AU - van Gassen, Koen L I

AU - Bakkers, Jeroen

AU - van Haaften, Gijs

PY - 2017/11

Y1 - 2017/11

N2 - 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.

AB - 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.

KW - Adolescent

KW - Animals

KW - Apoptosis

KW - Cell Cycle Checkpoints

KW - Child

KW - DNA Damage

KW - DNA Repair

KW - Developmental Disabilities

KW - Embryo, Nonmammalian

KW - Female

KW - Gene Expression Regulation, Developmental

KW - Genomic Instability

KW - Germ-Line Mutation

KW - Histones

KW - Humans

KW - Infant

KW - Intellectual Disability

KW - Microcephaly

KW - Mutation, Missense

KW - Nucleosomes

KW - Syndrome

KW - Zebrafish

KW - Journal Article

U2 - 10.1038/ng.3956

DO - 10.1038/ng.3956

M3 - Article

C2 - 28920961

SN - 1061-4036

VL - 49

SP - 1642

EP - 1646

JO - Nature Genetics

JF - Nature Genetics

IS - 11

ER -