BCL11A Haploinsufficiency Causes an Intellectual Disability Syndrome and Dysregulates Transcription

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.

BCL11A frameshift mutation associated with dyspraxia and hypotonia affecting the fine, gross, oral, and speech motor systems

“…Patients with missense and LoF variants of BCL11A described by Dias et al (2016) have global developmental delay, mostly moderate intellectual disability, and speech and language delay, as observed in our patient. Other signs include microcephaly (5/9) and mild facial dysmorphism.…”

“…Up to now, 11 patients with missense or loss‐of‐function (LoF) mutations of BCL11A have been reported (see OMIM #617101 and Dias et al [2016] for review), and a BCL11A haploinsufficiency related Intellectual Disability—Language Delay Disorder has been fully validated, in vivo, and in vitro (Dias et al, 2016). …”

“…Reported LoF mutations are scattered throughout the gene, whereas the pathological missense variants described so far are all located in the N‐terminal domain, necessary for dimerization of BCL11A isoforms and interaction with nucleosome remodeling complexes (Dias et al, 2016) (Figure 1A). A few LoF variants are also reported in the ExAC cohort (Lek et al, 2016): two at the very C‐distal portion of the BCL11A‐XL isoform (hg19, chr2:g.60687611G>C (p.Tyr812*); chr2:g.60687571G>A (p.Arg826*)), and one in the fifth exon of isoforms BCL11A‐L and‐ S (chr2:g.60679767delC, NM_018014.3:p.Arg756Glufs*22, NM_138559.1:p.Arg222Lysfs*17).…”

“…In the murine brain, Bcl11a controls cell polarity, radial migration of upper cortical neurons, axon branching, and dendrite outgrowth (Kuo, Chen, & Hsueh 2010; Kuo, Hong, & Hsueh, 2009; Kuo, Hong, Chien, & Hsueh, 2010; Wiegreffe et al, 2015). The DDD project (Deciphering Developmental Disorders Study, 2015; Dias et al, 2016) demonstrated that BCL11A haploinsufficiency causes intellectual disability and language delay (OMIM #617101). Patients with BCL11A mutations have global developmental delay, intellectual disability, which is moderate in most cases, and language delay of variable severity, with the occurrence of first words ranging from 16 months (mild) to only two words at the age of 6 years (severe).…”

“…(a) Figure adapted from Dias et al (2016). Schematic representation of the three major isoforms of BCL11A.…”