BCL11A Haploinsufficiency Causes an Intellectual Disability Syndrome and Dysregulates Transcription

Am J Hum Genet. 2016 Aug 4;99(2):253-74. doi: 10.1016/j.ajhg.2016.05.030.

Cristina Dias ¹, Sara B Estruch ², Sarah A Graham ², Jeremy McRae ¹, Stephen J Sawiak ³, Jane A Hurst ⁴, Shelagh K Joss ⁵, Susan E Holder ⁶, Jenny E V Morton ⁷, Claire Turner ⁸, Julien Thevenon ⁹, Kelly Mellul ¹⁰, Gabriela Sánchez-Andrade ¹, Ximena Ibarra-Soria ¹, Pelagia Deriziotis ², Rui F Santos ¹¹, Song-Choon Lee ¹², Laurence Faivre ⁹, Tjitske Kleefstra ¹³, Pentao Liu ¹, Mathew E Hurles ¹, DDD Study, Simon E Fisher ¹⁴, Darren W Logan ¹⁵

Affiliations

1 Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK.
2 Language and Genetics Department, Max Planck Institute for Psycholinguistics, PO Box 310, 6500 AH Nijmegen, the Netherlands.
3 Behavioural and Clinical Neuroscience Institute, University of Cambridge, Cambridge CB2 3EB, UK; Wolfson Brain Imaging Centre, University of Cambridge, Cambridge CB2 0QQ, UK.
4 North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Trust, London WC1N 3JH, UK.
5 West of Scotland Regional Genetics Service, Level 2 Laboratory Medicine Building, Queen Elizabeth University Hospital, Glasgow G51 4TF, UK.
6 North West Thames Regional Genetics Service, London North West Healthcare NHS Trust, Watford Rd, Harrow HA1 3UJ, UK.
7 West Midlands Regional Genetics Service, Birmingham Women's NHS Foundation Trust, Birmingham Women's Hospital, Edgbaston, Birmingham B15 2TG, UK.
8 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.
9 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.
10 Service de Génétique, Hôpital Necker-Enfants Malades, APHP, Institut Imagine, INSERM UMR1163, University Sorbonne-Paris-Cité, 75015 Paris, France.
11 Children's Radiology Department, Royal Manchester Children's Hospital, Manchester M13 9WL, UK.
12 Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK; Science Centre Singapore, 15 Science Centre Road, Singapore 609081, Singapore.
13 Department of Human Genetics, Radboud University Medical Center, 6500 HB Nijmegen, the Netherlands.
14 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: [email protected].
15 Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton CB10 1SA, UK. Electronic address: [email protected].

PMID: 27453576 DOI: 10.1016/j.ajhg.2016.05.030

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.

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