title: BCL11A Haploinsufficiency Causes an Intellectual Disability Syndrome and Dysregulates Transcription.
abstract: Intellectual disability (ID) is a common condition with considerable genetic heterogeneity. Next-generation sequencing of large cohorts has identified an increasing number of genes implicated in ID, but their roles in neurodevelopment remain largely unexplored. Here we report an ID syndrome caused by de novo heterozygous missense, nonsense, and frameshift mutations in BCL11A, encoding a transcription factor that is a putative member of the BAF swi/snf chromatin-remodeling complex. Using a comprehensive integrated approach to ID disease modeling, involving human cellular analyses coupled to mouse behavioral, neuroanatomical, and molecular phenotyping, we provide multiple lines of functional evidence for phenotypic effects. The etiological missense variants cluster in the amino-terminal region of human BCL11A, and we demonstrate that they all disrupt its localization, dimerization, and transcriptional regulatory activity, consistent with a loss of function. We show that Bcl11a haploinsufficiency in mice causes impaired cognition, abnormal social behavior, and microcephaly in accordance with the human phenotype. Furthermore, we identify shared aberrant transcriptional profiles in the cortex and hippocampus of these mouse models. Thus, our work implicates BCL11A haploinsufficiency in neurodevelopmental disorders and defines additional targets regulated by this gene, with broad relevance for our understanding of ID and related syndromes.
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK.
authors.forename: Cristina
authors.initials: C
authors.lastname: Dias
authors.affiliation: Language and Genetics Department, Max Planck Institute for Psycholinguistics, PO Box 310, 6500 AH Nijmegen, the Netherlands.
authors.forename: Sara B
authors.initials: SB
authors.lastname: Estruch
authors.affiliation: Language and Genetics Department, Max Planck Institute for Psycholinguistics, PO Box 310, 6500 AH Nijmegen, the Netherlands.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Graham
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK.
authors.forename: Jeremy
authors.initials: J
authors.lastname: McRae
authors.affiliation: Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge CB2 3EB, UK; Wolfson Brain Imaging Centre, University of Cambridge, Cambridge CB2 0QQ, UK.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Sawiak
authors.affiliation: North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UK.
authors.forename: Jane A
authors.initials: JA
authors.lastname: Hurst
authors.affiliation: West of Scotland Regional Genetics Service, Level 2 Laboratory Medicine Building, Queen Elizabeth University Hospital, Glasgow G51 4TF, UK.
authors.forename: Shelagh K
authors.initials: SK
authors.lastname: Joss
authors.affiliation: North West Thames Regional Genetics Service, London North West Healthcare NHS Trust, Watford Rd, Harrow HA1 3UJ, UK.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Holder
authors.affiliation: West Midlands Regional Genetics Service, Birmingham Women's NHS Foundation Trust, Birmingham Women's Hospital, Edgbaston, Birmingham B15 2TG, UK.
authors.forename: Jenny E V
authors.initials: JE
authors.lastname: Morton
authors.affiliation: Peninsula Clinical Genetics Service, Department of Clinical Genetics, Royal Devon and Exeter NHS Foundation Trust, Clinical Genetics Department, Royal Devon & Exeter Hospital (Heavitree), Gladstone Road, Exeter EX1 2ED, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Turner
authors.affiliation: Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Centre Hospitalier Universitaire Dijon, 21079 Dijon, France; Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'Interrégion Est, Centre Hospitalier Universitaire Dijon, 21079 Dijon, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Thevenon
authors.affiliation: Service de Génétique, Hôpital Necker-Enfants Malades, APHP, Institut Imagine, INSERM UMR1163, University Sorbonne-Paris-Cité, 75015 Paris, France.
authors.forename: Kelly
authors.initials: K
authors.lastname: Mellul
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Sánchez-Andrade
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK.
authors.forename: Ximena
authors.initials: X
authors.lastname: Ibarra-Soria
authors.affiliation: Language and Genetics Department, Max Planck Institute for Psycholinguistics, PO Box 310, 6500 AH Nijmegen, the Netherlands.
authors.forename: Pelagia
authors.initials: P
authors.lastname: Deriziotis
authors.affiliation: Children's Radiology Department, Royal Manchester Children's Hospital, Manchester M13 9WL, UK.
authors.forename: Rui F
authors.initials: RF
authors.lastname: Santos
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK; Science Centre Singapore, 15 Science Centre Road, Singapore 609081, Singapore.
authors.forename: Song-Choon
authors.initials: SC
authors.lastname: Lee
authors.affiliation: Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement (TRANSLAD), Centre Hospitalier Universitaire Dijon, 21079 Dijon, France; Centre de Génétique et Centre de Référence Anomalies du Développement et Syndromes Malformatifs de l'Interrégion Est, Centre Hospitalier Universitaire Dijon, 21079 Dijon, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Faivre
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
authors.forename: Tjitske
authors.initials: T
authors.lastname: Kleefstra
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK.
authors.forename: Pentao
authors.initials: P
authors.lastname: Liu
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK.
authors.forename: Mathew E
authors.initials: ME
authors.lastname: Hurles
authors.affiliation: Language and Genetics Department, Max Planck Institute for Psycholinguistics, PO Box 310, 6500 AH Nijmegen, the Netherlands; Donders Institute for Brain, Cognition and Behaviour, 6525 EN Nijmegen, the Netherlands. Electronic address: simon.fisher@mpi.nl.
authors.forename: Simon E
authors.initials: SE
authors.lastname: Fisher
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK. Electronic address: dl5@sanger.ac.uk.
authors.forename: Darren W
authors.initials: DW
authors.lastname: Logan
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly / Q000235:genetics; D018389:Codon, Nonsense / Q000235:genetics; D003072:Cognition Disorders / Q000235:genetics; D016368:Frameshift Mutation / Q000235:genetics; D057895:Haploinsufficiency / Q000235:genetics*; D006624:Hippocampus / Q000378:metabolism; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000473:pathology / Q000523:psychology; D008297:Male; D051379:Mice; D008831:Microcephaly / Q000235:genetics; D020125:Mutation, Missense / Q000235:genetics; D065886:Neurodevelopmental Disorders / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D009687:Nuclear Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D012097:Repressor Proteins; D012919:Social Behavior; D013577:Syndrome; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D059467:Transcriptome
chemical_list: C486563:BCL11A protein, human; D002352:Carrier Proteins; D018389:Codon, Nonsense; D009687:Nuclear Proteins; D012097:Repressor Proteins; D014157:Transcription Factors