BRD4 interacts with NIPBL and BRD4 is mutated in a Cornelia de Lange-like syndrome

Gabrielle Olley; Morad Ansari; Hemant Bengani; Graeme R Grimes; James Rhodes; Alex von Kriegsheim; Ana Blatnik; Fiona J Stewart; Emma Wakeling; Nicola Carroll; Alison Ross; Soo-Mi Park; Deciphering Developmental Disorders Study; Wendy A Bickmore; Madapura M Pradeepa; David R FitzPatrick

doi:10.1038/s41588-018-0042-y

BRD4 interacts with NIPBL and BRD4 is mutated in a Cornelia de Lange-like syndrome

Nat Genet. 2018 Mar;50(3):329-332. doi: 10.1038/s41588-018-0042-y. Epub 2018 Jan 29.

Authors

Gabrielle Olley^#¹, Morad Ansari^#¹, Hemant Bengani¹, Graeme R Grimes², James Rhodes³, Alex von Kriegsheim², Ana Blatnik^{1

4}, Fiona J Stewart⁵, Emma Wakeling⁶, Nicola Carroll⁷, Alison Ross⁸, Soo-Mi Park⁹; Deciphering Developmental Disorders Study; Wendy A Bickmore¹⁰, Madapura M Pradeepa^{11

12}, David R FitzPatrick¹³

Affiliations

¹ MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Edinburgh, UK.
² MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Edinburgh, UK.
³ Department of Biochemistry, Oxford University, Oxford, UK.
⁴ Cancer Genetics Clinic, Institute of Oncology, Ljubljana, Slovenia.
⁵ Department of Medical Genetics, Belfast City Hospital, Belfast, UK.
⁶ North West Thames Regional Genetics Service, London North West Healthcare NHS Trust, Harrow, UK.
⁷ South East Scotland Regional Genetics Services, Western General Hospital, Edinburgh, UK.
⁸ Department of Medical Genetics, Ashgrove House, Foresterhill, Aberdeen, UK.
⁹ East Anglian Medical Genetics Service, Clinical Genetics, Addenbrooke's Treatment Centre, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.
¹⁰ MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Edinburgh, UK. [email protected].
¹¹ MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Edinburgh, UK. [email protected].
¹² School of Biological Sciences, University of Essex, Colchester, UK. [email protected].
¹³ MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine at the University of Edinburgh, Edinburgh, UK. [email protected].

^# Contributed equally.

Abstract

We found that the clinical phenotype associated with BRD4 haploinsufficiency overlapped with that of Cornelia de Lange syndrome (CdLS), which is most often caused by mutation of NIPBL. More typical CdLS was observed with a de novo BRD4 missense variant, which retained the ability to coimmunoprecipitate with NIPBL, but bound poorly to acetylated histones. BRD4 and NIPBL displayed correlated binding at super-enhancers and appeared to co-regulate developmental gene expression.

Publication types

Case Reports
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Binding Sites / genetics
Cell Cycle Proteins
Cells, Cultured
Child
Child, Preschool
De Lange Syndrome / genetics*
Enhancer Elements, Genetic
Female
Gene Expression Regulation, Developmental
Haploinsufficiency
Humans
Male
Mice
Mice, Transgenic
Mutation, Missense*
Nuclear Proteins / genetics*
Nuclear Proteins / metabolism*
Pedigree
Phenotype
Protein Binding
Proteins / metabolism*
Transcription Factors / genetics*
Transcription Factors / metabolism*

Substances

BRD4 protein, human
Cell Cycle Proteins
NIPBL protein, human
Nuclear Proteins
Proteins
Transcription Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding