Skip Header

You are using a version of browser that may not display all the features of this website. Please consider upgrading your browser.

BCL11A haploinsufficiency causes an intellectual disability syndrome and dysregulates transcription.

DDD Study

Dias C., Estruch S.B., Grmaham S.A., McRae J., Sawiak S.J., Hurst J.A., Joss S.K., Holder S.E., Morton J.E., Turner C., Thevenon J., Mellul K., Sanchez-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.

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.

Am. J. Hum. Genet. 99:253-274(2016) [PubMed] [Europe PMC]

UniProt is an ELIXIR core data resource
Main funding by: National Institutes of Health

We'd like to inform you that we have updated our Privacy Notice to comply with Europe’s new General Data Protection Regulation (GDPR) that applies since 25 May 2018.

Do not show this banner again