Alt. symbols: ZNF856B | CTIP-2 | CTIP2 | hRIT1-alpha

Approved name: BCL11 transcription factor B
Alt. names: B-cell CLL/lymphoma 11B (zinc finger protein), B cell CLL/lymphoma 11B, BCL11B, BAF complex component

Location: 14q32.2: 99169287 - 99272197 (-)
Gene type: protein_coding, 3 transcripts.

Scores: LoFtool: | pLI: 0.92978524 | LOEUF: 0.282

HGNC: 13222

NCBI: 64919, RefSeq: NG_027894.1

Ensembl: ENSG00000127152.18

LRG_ | Status: none

OMIM: 606558

Expression | ProteinAtlas

BCL11B encodes a C2H2-type zinc finger protein that acts as transcriptional activator and repressor across multiple lineages at various points in pre- and post-natal development, particularly in the nervous and immune systems. BCL11B exists as 2 primary isoforms, the shorter alpha form of which excludes Exon 3 (encoding a Pro-rich region) by alternative splicing. Of its 6 zinc finger domains, the most N-terminal one is thought to be involved in homodimerization, the 2nd and 3rd in DNA-binding and the 3 C-terminal ones in mediating other protein-protein interactions (PMID: 29203643, 23211040). BCL11B has been shown in mouse models to localize to the cerebral cortex, the limbic system, basal ganglia, olfactory bulb, hippocampus and dorsal cells of the spinal cord from developing embryos into adulthood (PMID: 15465497). It has been implicated in axonal pathfinding and corticospinal motor neuron development (PMID: 15534207), specification and maintenance of cerebral GABAergic interneurons (PMID: 1374971, 26698402), postnatal hippocampal neurogenesis (PMID: 22588081). It is also important for the lineage commitment, differentiation and survival of T lymphocytes during thymocyte development, partly via its role in promoting IL2 expression (PMID: 12717433, 16809611, 20595614). Bcl11b deficiency results in developmental arrest of early T cell progenitors at the DN2 stage and their reorientation towards acquisition of myeloid or natural killer (NK) cell features (PMID: 20595615, 20538915). BCL11B has also been shown to be important for post-selection CD4 vs CD8 T cell lineage choice through its regulation of ThPOK and Runx3 (PMID: 28951542). BCL11B has also been implicated in the development of invariant natural killer T (iNKT) cells (PMID: 21444811), regulatory T cells (PMID: 21875956), and type 2 innate lymphoid cells (PMID: 26231117, 25964371). Punwani et al. (2016) also suggested that BCL11B is important for hematopoietic stem cell responsiveness to chemotactic signals by controlling expression of genes such as CCR7 and CCR9, which encode receptors whose activation directs progenitor cells to migrate from the bone marrow to the thymus (PMID: 27959755). BCL11B has also been shown to harbor roles osteogenic mesenchyme development, with Bcl11b-deficient mouse models showing osteoprogenitor proliferation, premature osteoblast differentiation and enhanced skull mineralization, leading to craniosynostoses (PMID: 26453795). Moreover, both global and epidermal keratinocyte-specific Bcl11b ablation in mouse models was shown to cause a skin phenotype of atopic dermatitis-like inflammation with extensive immune cell infiltration (PMID: 23096701), at least partly related to its role in regulating the expression of genes important for skin sphingolipid biosynthesis and barrier function (PMID: 23284675) as well as genes directing keratinocyte proliferation and differentiation (PMID: 23015591).

Monoallelic variants in BCL11B are associated with a multi-system syndrome featuring developmental delays, intellectual disability, dysmorphic features, and vision abnormalities [OMIM: 618092]) with or without immunodeficiency in some patients [OMIM: 617237] (, 29985992, 31347296). Punwani et al. (2016) identified a de novo heterozygous missense variant (p.N441K) in a male infant with “leaky” SCID, craniofacial and dermal abnormalities, absent corpus callosum and other brain anomalies, developme ntal delays (including both expressive and receptive language), intellectual impairment, spastic quadriplegia and seizures (PMID: 27959755). He was successfully transplanted with hematopoietic stem cells from a matched unrelated donor with full T-cell engraftment and TCR repertoire diversity but this only ameliorated the immune phenotype. The authors used over-expression assays and ChIP to show that the mutant allele exerted both dominant negative and neomorphic effects on wild-type (WT) BCL11B DNA-binding activity, blocking binding to canonical sites and redirecting binding to novel sites. This presumably led to the T cell developmental arrest and hematopoietic stem cell migration defects modeled in human cells and zebrafish. Moreover, over-expression of a WT but not mutant construct rescued many of the phenotypic defects modeled in zebrafish embryos. Lessel et al. (2018) described 13 additional patients with global developmental delays, speech impairment and intellectual disability, all of whom harbored heterozygous frameshift or nonsense mutations, presumed to cause loss-of-function via either haploinsufficiency or truncation. However, the authors presented no experimental evidence demonstrating that truncation mutants escaping nonsense-mediated decay and losing C-terminal zinc finger domains could not also exert dominant negative effects. All were inherited de novo except for one patient with a frameshift mutation inherited from a similarly affected mother (PMID: 29985992). Though 3 of these patients harbored a reported history of recurrent or atypical infections, none showed overt signs of immunodeficiency except for one patient found to have low TRECs at birth who harbored a N807K change in an alpha-helix-containing DNA recognition site within the 4th zinc finger domain. However, more extensive immunophenotyping identified T cell subset abnormalities, including reduced proportions of CD4+ recent thymic emigrants, an overrepresentation of γδ T cells, changes in the frequency of effector T cells, and a lack of peripheral type 2 innate lymphoid cells (ILC2s), consistent with the findings previously described in Bcl11b-deficient mice. Qiao et al. (2019) identified another de novo heterozygous frameshift variant presumed to result in a truncation mutant in a Chinese girl with craniofacial abnormalities, developmental delays, intellectual disability and anecdotal history of more frequent respiratory infections but without requiring significant medical management (PMID: 31347296). Most recently, Lu et al. (2021) noted that 8 of the 17 previously published patients presented with atopic disease, including asthma, eosinophilia, food allergies, and eczema suggestive of exacerbated Th2 responses (PMID: 34887873). They reported a de novo heterozygous missense variant (C826Y) in a female patient with severe atopic disease, neurodevelopmental abnormalities, and immune dysregulation. Though in-depth T cell immunophenotyping showed normal TREC an [Load More]