BCL11A Haploinsufficiency Causes an Intellectual Disability Syndrome and Dysregulates Transcription

2.50
Hdl Handle:
http://hdl.handle.net/11287/617691
Title:
BCL11A Haploinsufficiency Causes an Intellectual Disability Syndrome and Dysregulates Transcription
Authors:
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.
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.
Citation:
BCL11A Haploinsufficiency Causes an Intellectual Disability Syndrome and Dysregulates Transcription 2016 Aug;99(2): 253-274 The American Journal of Human Genetics
Publisher:
Elsevier
Journal:
The American Journal of Human Genetics
Issue Date:
21-Jul-2016
URI:
http://hdl.handle.net/11287/617691
DOI:
10.1016/j.ajhg.2016.05.030
Additional Links:
http://linkinghub.elsevier.com/retrieve/pii/S0002929716302014
Note:
This article is available via Open Access. Click on the Additional Link above to access the full-text via the publisher's site.
Type:
Journal Article
Language:
en
ISSN:
00029297
Appears in Collections:
Clinical Genetics (Peninsula Genetics); 2016 RD&E publications

Full metadata record

DC FieldValue Language
dc.contributor.authorDias, C.en
dc.contributor.authorEstruch, S. B.en
dc.contributor.authorGraham, S. A.en
dc.contributor.authorMcRae, J.en
dc.contributor.authorSawiak, S. J.en
dc.contributor.authorHurst, J. A.en
dc.contributor.authorJoss, S. K.en
dc.contributor.authorHolder, S. E.en
dc.contributor.authorMorton, J. E.V.en
dc.contributor.authorTurner, Claire L.en
dc.contributor.authorThevenon, J.en
dc.contributor.authorMellul, K.en
dc.contributor.authorSánchez-Andrade, G.en
dc.contributor.authorIbarra-Soria, X.en
dc.contributor.authorDeriziotis, P.en
dc.contributor.authorSantos, R. F.en
dc.contributor.authorLee, S-C.en
dc.contributor.authorFaivre, L.en
dc.contributor.authorKleefstra, T.en
dc.contributor.authorLiu, P.en
dc.contributor.authorHurles, M. E.en
dc.contributor.authorFisher, S.E.en
dc.contributor.authorLogan, D.W.en
dc.date.accessioned2016-07-28T13:03:22Z-
dc.date.available2016-07-28T13:03:22Z-
dc.date.issued2016-07-21-
dc.identifier.citationBCL11A Haploinsufficiency Causes an Intellectual Disability Syndrome and Dysregulates Transcription 2016 Aug;99(2): 253-274 The American Journal of Human Geneticsen
dc.identifier.issn00029297-
dc.identifier.doi10.1016/j.ajhg.2016.05.030-
dc.identifier.urihttp://hdl.handle.net/11287/617691-
dc.description.abstractIntellectual 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.en
dc.language.isoenen
dc.publisherElsevieren
dc.relation.urlhttp://linkinghub.elsevier.com/retrieve/pii/S0002929716302014en
dc.rightsArchived 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/).en
dc.subjectWessex Classification Subject Headings::Oncology. Pathology.::Geneticsen
dc.titleBCL11A Haploinsufficiency Causes an Intellectual Disability Syndrome and Dysregulates Transcriptionen
dc.typeJournal Articleen
dc.identifier.journalThe American Journal of Human Geneticsen
dc.description.noteThis article is available via Open Access. Click on the Additional Link above to access the full-text via the publisher's site.en
dc.description.fundingWellcome Trust (grant number WT098051)en
dc.type.versionIn press (epub ahead of print)en
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