BCL11A Haploinsufficiency Causes an Intellectual Disability Syndrome and Dysregulates Transcription
Author
Dias, C.
Estruch, S. B.
Graham, S. A.
McRae, J.
Sawiak, S. J.
Hurst, J. A.
Joss, S. K.
Holder, S. E.
Morton, J. E.V.
Turner, Claire L.
Thevenon, J.
Mellul, K.
Sánchez-Andrade, G.
Ibarra-Soria, X.
Deriziotis, P.
Santos, R. F.
Lee, S-C.
Faivre, L.
Kleefstra, T.
Liu, P.
Hurles, M. E.
Fisher, S.E.
Logan, D.W.
Date
2016-07-21Journal
The American Journal of Human GeneticsType
Journal ArticlePublisher
ElsevierDOI
10.1016/j.ajhg.2016.05.030Rights
Archived with thanks to The American Journal of Human Genetics.This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Metadata
Show full item recordAbstract
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.