BCL11A Haploinsufficiency Causes an Intellectual Disability Syndrome and Dysregulates Transcription - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue American Journal of Human Genetics Année : 2016

BCL11A Haploinsufficiency Causes an Intellectual Disability Syndrome and Dysregulates Transcription

, , , , , , , , , , (1) , , , , , , , (2) , (3) , , , (4) , (5)
1
2
3
4
5
Cristina Dias
  • Fonction : Auteur
Sara b. Estruch
  • Fonction : Auteur
Sarah a. Graham
  • Fonction : Auteur
Jeremy Mcrae
  • Fonction : Auteur
Stephen j. Sawiak
  • Fonction : Auteur
Jane a. Hurst
  • Fonction : Auteur
Shelagh k. Joss
  • Fonction : Auteur
Susan e. Holder
  • Fonction : Auteur
Jenny e.V. Morton
  • Fonction : Auteur
Claire Turner
  • Fonction : Auteur
Kelly Mellul
  • Fonction : Auteur
Gabriela Sánchez-Andrade
  • Fonction : Auteur
Ximena Ibarra-Soria
  • Fonction : Auteur
Pelagia Deriziotis
  • Fonction : Auteur
Rui f. Santos
  • Fonction : Auteur
Song-Choon Lee
  • Fonction : Auteur
Tjitske Kleefstra
  • Fonction : Auteur
  • PersonId : 916703
Pentao Liu
  • Fonction : Auteur
Mathew e. Hurles
  • Fonction : Auteur

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.

Dates et versions

hal-01680178 , version 1 (10-01-2018)

Identifiants

Citer

Cristina Dias, Sara b. Estruch, Sarah a. Graham, Jeremy Mcrae, Stephen j. Sawiak, et al.. BCL11A Haploinsufficiency Causes an Intellectual Disability Syndrome and Dysregulates Transcription. American Journal of Human Genetics, 2016, 99 (2), pp.253 - 274. ⟨10.1016/j.ajhg.2016.05.030⟩. ⟨hal-01680178⟩
107 Consultations
0 Téléchargements

Altmetric

Partager

Gmail Facebook Twitter LinkedIn More