Fiche publication
Date publication
août 2016
Journal
American journal of human genetics
Auteurs
Membres identifiés du Cancéropôle Est :
Pr FAIVRE Laurence
Tous les auteurs :
Dias C, Estruch SB, Graham SA, McRae J, Sawiak SJ, Hurst JA, Joss SK, Holder SE, Morton JE, Turner C, Thevenon J, Mellul K, Sánchez-Andrade G, Ibarra-Soria X, Deriziotis P, Santos RF, Lee SC, Faivre L, Kleefstra T, Liu P, Hurles ME, ,Fisher SE, Logan DW
Lien Pubmed
Résumé
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.
Mots clés
Animals, Carrier Proteins, chemistry, Cerebral Cortex, metabolism, Chromatin Assembly and Disassembly, genetics, Codon, Nonsense, genetics, Cognition Disorders, genetics, Frameshift Mutation, genetics, Haploinsufficiency, genetics, Hippocampus, metabolism, Humans, Intellectual Disability, genetics, Male, Mice, Microcephaly, genetics, Mutation, Missense, genetics, Neurodevelopmental Disorders, genetics, Nuclear Proteins, chemistry, Phenotype, Social Behavior, Syndrome, Transcription Factors, chemistry, Transcription, Genetic, Transcriptome
Référence
Am. J. Hum. Genet.. 2016 08 4;99(2):253-74
