RRC ID 51252
Author Tessadori F, Giltay JC, Hurst JA, Massink MP, Duran K, Vos HR, van Es RM, Deciphering Developmental Disorders Study, Scott RH, van Gassen KLI, Bakkers J, van Haaften G.
Title Germline mutations affecting the histone H4 core cause a developmental syndrome by altering DNA damage response and cell cycle control.
Journal Nat Genet
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.
Volume 49(11)
Pages 1642-1646
Published 2017-11
DOI 10.1038/ng.3956
PII ng.3956
PMID 28920961
MeSH Adolescent Animals Apoptosis Cell Cycle Checkpoints Child DNA Damage DNA Repair* Developmental Disabilities / diagnosis Developmental Disabilities / genetics* Developmental Disabilities / metabolism Developmental Disabilities / pathology Embryo, Nonmammalian Female Gene Expression Regulation, Developmental Genomic Instability Germ-Line Mutation Histones / genetics* Histones / metabolism Humans Infant Intellectual Disability / diagnosis Intellectual Disability / genetics* Intellectual Disability / metabolism Intellectual Disability / pathology Microcephaly / diagnosis Microcephaly / genetics* Microcephaly / metabolism Microcephaly / pathology Mutation, Missense* Nucleosomes / chemistry Nucleosomes / metabolism Syndrome Zebrafish / genetics Zebrafish / growth & development
IF 25.455
Times Cited 11
Zebrafish Tg(EF1α:mKO2-zCdt1(1/190)) Tg(EF1α:mAG-hGem(1/60))