A de novo loss-of-function variant in the BCL11A gene has been identified in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). This gene was also identified in an ASD whole-exome sequencing study and subsequent TADA (transmission and de novo association) analysis as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of <0.1 (De Rubeis et al., 2014).
Molecular Function
This gene encodes a C2H2 type zinc-finger protein by its similarity to the mouse Bcl11a/Evi9 protein that functions as a myeloid and B-cell proto-oncogene. BCL11A resides within the dyslexia susceptibility candidate region 3 (DYX3) and has been proposed to be a candidate gene in chromosome 2p16.1-p15 deletion syndrome.
External Links
References
Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
De novo gene disruptions in children on the autistic spectrum.
450 epilepsy cases of Han Chinese descent diagnosed at the First Affiliated Hospital of Kunming Medical University and Xinqiao Hospital and 550 ethnically-matched controls from the same hospitals.
Haploinsufficiency of Bcl11a in a mouse model recapitulates cognitive, behavioral, and neuroanatomical phenotypes present in BCL11A happloinsufficient humans. Haploinsufficiency of Bcl11a in a mouse model causes transcriptional dysregulation of the hippocampus and cortex, brain regions that correlate with neuroanatomical and behavioral phenotypes of ASD.
References
Type
Title
Author, Year
Additional
Bcl11a is essential for normal lymphoid development.
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Exon1 of Bcl11a gene containing the translation start site and encoding the first 18 amino acids of the Bcl11a protein, was deleted using homologous recombination, it was replaced with a PGK-new-bpA cassette.
Allele Type: Targeted (knockout)
Strain of Origin: Genetic Background: 129/SvJ*C57BL/6J
ES Cell Line: CJ7
Mutant ES Cell Line: Model Source:
Model Type:
Genetic
Model Genotype:
Heterozygous
Mutation:
Bcl11a heterozygous mouse line have a Bcl11a gene trap including a lacz reporter flanked by FRT sites, upstream of exon 4, disrupting all major isoforms.
Allele Type: Targeted (knockout)
Strain of Origin: 129/SvJ
Genetic Background: C57Bl/6*129S5
ES Cell Line: Unreported
Mutant ES Cell Line: Unreported
Model Source: Sanger Institute
Model Type:
Genetic
Model Genotype:
Homozygous
Mutation:
Bcl11a cko mice were generated by crossing datires-cre mice with bcl11aflox mice (genotype: datires-cre/+, bcl11aflox/flox).
Allele Type: Conditional knockout
Strain of Origin: Genetic Background: C57BL6/CD1
ES Cell Line: Mutant ES Cell Line: Model Source: 16865686
Model Type:
Genetic
Model Genotype:
Compound heterozygous
Mutation:
In a subset of bcl11a cko mice, the bcl11alacz null allele was introduced by crossing datires-cre mice with bcl11aflox/lacz mice (genotype: datires-cre/+, bcl11aflox/lacz). in this model bcl11a-expressing mda population expresses b-gal even after inactivation of bcl11a, allowing analysis of the effect of bcl11a inactivation specifically in midbrain dopaminergic neurons that would normally express bcl11a.
Allele Type: Conditional knockout
Strain of Origin: Genetic Background: C57BL6/CD1
ES Cell Line: Mutant ES Cell Line: Model Source: 27453576
Development of immune cells and primary lymphoid organs1
Decreased
Description: Early development of b cells in fetal liver is severely affected in bcl11a null embryos as the earliest b cell lineage marker: b220 expression has very low expression
Exp Paradigm: NA
Description: Bcl11a ht ki mice show increased movement in an open field compared to wildtype controls
Exp Paradigm: A period of movement was defined when the mouse reached a velocity of 2 cm/s over two frames
Description: Bcl11a ht ki mice show increased locomotion in an open field compared to wildtype controls
Exp Paradigm: A period of movement was defined when the mouse reached a velocity of 2 cm/s over two frames
Description: Bcl11a ht ki mice have smaller posterior cortical amygdaloid nuclei compared to control mice
Exp Paradigm: Upon normalizing by overall brain volume per genotype, changes in volumes of specific substructures were measured
Description: Bcl11a ht ki mice have smaller overall brain volume (reflecting decreases in white and gray matters) than controls, bcl11a ht ki skulls are smaller in width but not in length compared to controls without any malformations
Exp Paradigm: Ex vivo imaging of whole mouse heads using magnetic resonance imaging (mri) tensor-based morphometry followed by voxel-based quantification of brain volume was performed
Description: Bcl11a ht ki mice have smaller corpus callossum volumes than control mice
Exp Paradigm: Upon normalizing by overall brain volume per genotype, changes in volumes of specific substructures were measured
Description: Bcl11a ht ki mice have smaller hippocampus (corresponding to ca1, ca2, ca3, and the fimbria) compared to control mice although the cellular layers are not changed in the bcl11a ht ki mice
Exp Paradigm: Upon normalizing by overall brain volume per genotype, changes in volumes of specific substructures were measured
Description: Bcl11a ht ki mice have smaller ventral and midline thalamic nuclei compared to control mice
Exp Paradigm: Upon normalizing by overall brain volume per genotype, changes in volumes of specific substructures were measured
Description: Bcl11a ht ki mice have a smaller cerebellum, including regions of the superior vermis, compared to control mice
Exp Paradigm: Upon normalizing by overall brain volume per genotype, changes in volumes of specific substructures were measured
Description: Bcl11a ht ki mice were unable to differentiate between the familiar and unfamiliar stimulus mice 24 hours after habituation whereas wt controls could
Exp Paradigm: Preference index (pi) = (time in chamber with object containing a conspecific stimulus - time in chamber with object only)/(time in chamber with object containing a conspecific stimulus + time in chamber with object only)
Description: Bcl11a ht ki mice have decreased preference for a conspecfic mouse compared to an empty chamber spending a similar amount of time in both chambers, compared to the wildtype controls
Exp Paradigm: NA
Description: Bcl11a ht ki mice have a shift in bcl11a localization toward deeper cortical layers (layers v and vi) relative to more superficial layers (ii/iii, iv) in wt controls
Exp Paradigm: Bcl11a immunostaining
Description: Bcl11a ht ki mice show abnormal transcriptome profiles in the hippocampus and cortex: 608 differentiatially expressed genes were identified in the cortex, 157 upregulated and 451 downregulated in bcl11a ht ki mice compared to controls, 442 differentiatially expressed genes were identified in the hippocampus, 183 upregulated and 259 downregulated in bcl11a ht ki mice compared to controls
Exp Paradigm: Six samples per genotype were used for the hippocampus and nine samples per genotype for the cortex
Description: Bcl11a cko mice were not able to learn the motor task because the time to fall did not increase in bcl11a cko mice within the 5 days of the trial period
Description: Loss of th+ neurons was significantly more pronounced (4,231 ± 208.2 cells) in bcl11a cko mice versus control (5,086 ± 292.8 cells); total nissl stained neuron number declined by 12% (from 9,185 ± 141.4 to 8,070 ± 525.6) and 27% (to 6,741 ± 326.1) in the lesioned pars compacta of the substantia nigra of control and bcl11a cko mice, respectively; density of labeled neurons was decreased in the right pars compacta of the substantia nigra of bcl11a cko mice as compared to control mice
Exp Paradigm: unilateral intraparenchymal injection of rAAVs carrying the DNA for human a-synuclein targeted to the right pars compacta of the substantia nigra; TH+ neurons; Nissl stained neurons; antibody recognizing a-synuclein phosphorylated at Ser129+
Description: Bcl11a mrna and protein is still expressed in cerebral cortex neurons of bcl11a ckoflox mice but absent in midbrain dompaminergic neurons of bcl11a cko mice
Exp Paradigm: multiplex fluorescent in situ hybridization
Description: Bcl11a-midbrain dopaminergic neurons were shifted from medial to lateral in the rostral pars compacta of the substantia nigra as compared to controls in bcl11a cko lacz mice
Description: Percentage of bcl11a-midbrain dopaminergic neurons is significantly increased in the caudal linear neurons of bcl11a cko lacz mice as compared to those of bcl11a-lacz mice
Description: A-synuclein toxicity caused a more severe loss of th-positive neurons in the pars compacta of the substantia nigra of bcl11a cko lacz mice than that of bcl11a-lacz controls; 30% of b-gal+ neurons (from 1,899 ± 70.8 to 1,332 ± 93.7 cells) degenerated because of a-synuclein overexpression, whereas no statistically significant changes were observed in the number of b-gal midbrain dopaminergic cells between the lesioned and intact pars compacta of the substantia nigra; a-synuclein toxicity killed almost 65% (from 1,899 to 664 ± 117.0 cells) and 34% (from 4,055 to 2,685 ± 91.4 cells) of b-gal+ and b-gal cells, respectively
Exp Paradigm: unilateral intraparenchymal injection of rAAVs carrying the DNA for human a-synuclein targeted to the right pars compacta of the substantia nigra
