Bcl11b—A Critical Neurodevelopmental Transcription Factor—Roles in Health and Disease

Lennon, Matthew J; Jones, Simon P.; Lovelace, Michael D.; Guillemin, Gilles J.; Brew, Bruce J.

doi:10.3389/fncel.2017.00089

Cited by 54 publications

(42 citation statements)

References 67 publications

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“…These Ctip2-deficient neurons characteristically display reduced expression of calbindin 1 (Calb1), which plays important roles in neuro-behavioral and memory formation (Simon et al, 2012 ; Soontornniyomkij et al, 2012 ). On the whole, loss of Ctip2 during development of the hippocampus leads to dramatic reduction in size and neuronal pool of the DG, and impairment of spatial memory formation (Simon et al, 2012 , 2016 ; Lennon et al, 2017 ).…”

Section: Function Of Baf Complex(es) In Development Of the Nervous Symentioning

confidence: 99%

Chromatin Remodeling BAF (SWI/SNF) Complexes in Neural Development and Disorders

Sokpor

Xie

Rosenbusch

et al. 2017

Front. Mol. Neurosci.

189

170

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The ATP-dependent BRG1/BRM associated factor (BAF) chromatin remodeling complexes are crucial in regulating gene expression by controlling chromatin dynamics. Over the last decade, it has become increasingly clear that during neural development in mammals, distinct ontogenetic stage-specific BAF complexes derived from combinatorial assembly of their subunits are formed in neural progenitors and post-mitotic neural cells. Proper functioning of the BAF complexes plays critical roles in neural development, including the establishment and maintenance of neural fates and functionality. Indeed, recent human exome sequencing and genome-wide association studies have revealed that mutations in BAF complex subunits are linked to neurodevelopmental disorders such as Coffin-Siris syndrome, Nicolaides-Baraitser syndrome, Kleefstra's syndrome spectrum, Hirschsprung's disease, autism spectrum disorder, and schizophrenia. In this review, we focus on the latest insights into the functions of BAF complexes during neural development and the plausible mechanistic basis of how mutations in known BAF subunits are associated with certain neurodevelopmental disorders.

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Section: Function Of Baf Complex(es) In Development Of the Nervous Symentioning

confidence: 99%

Chromatin Remodeling BAF (SWI/SNF) Complexes in Neural Development and Disorders

Sokpor

Xie

Rosenbusch

et al. 2017

Front. Mol. Neurosci.

189

170

View full text Add to dashboard Cite

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“…BCL11B (RefSeq NM_138576.3, MIM 606558) is a lineage-specific, Krü ppel-like C2H2 zinc-finger-containing transcriptional regulator of different physiological processes including apoptosis, cell proliferation, and differentiation (Lennon et al, 2017). Biallelic loss of Bcl11b leads to perinatal lethality in mice, accompanied by defects in the development of the CNS (Arlotta et al, 2005;Simon et al, 2012), the epidermis (Golonzhka et al, 2009a), the teeth (Golonzhka et al, 2009b), as well as in the development and maintenance of the T cell lineage (Wakabayashi et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

BCL11B mutations in patients affected by a neurodevelopmental disorder with reduced type 2 innate lymphoid cells

Lessel

Gehbauer

Bramswig

et al. 2018

Brain

101

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The transcription factor BCL11B is essential for development of the nervous and the immune system, and Bcl11b deficiency results in structural brain defects, reduced learning capacity, and impaired immune cell development in mice. However, the precise role of BCL11B in humans is largely unexplored, except for a single patient with a BCL11B missense mutation, affected by multisystem anomalies and profound immune deficiency. Using massively parallel sequencing we identified 13 patients bearing heterozygous germline alterations in BCL11B. Notably, all of them are affected by global developmental delay with speech impairment and intellectual disability; however, none displayed overt clinical signs of immune deficiency. Six frameshift mutations, two nonsense mutations, one missense mutation, and two chromosomal rearrangements resulting in diminished BCL11B expression, arose de novo. A further frameshift mutation was transmitted from a similarly affected mother. Interestingly, the most severely affected patient harbours a missense mutation within a zinc-finger domain of BCL11B, probably affecting the DNA-binding structural interface, similar to the recently published patient. Furthermore, the most C-terminally located premature termination codon mutation fails to rescue the progenitor cell proliferation defect in hippocampal slice cultures from Bcl11b-deficient mice. Concerning the role of BCL11B in the immune system, extensive immune phenotyping of our patients revealed alterations in the T cell compartment and lack of peripheral type 2 innate lymphoid cells (ILC2s), consistent with the findings described in Bcl11b-deficient mice. Unsupervised analysis of 102 T lymphocyte subpopulations showed that the patients clearly cluster apart from healthy children, further supporting the common aetiology of the disorder. Taken together, we show here that mutations leading either to BCL11B haploinsufficiency or to a truncated BCL11B protein clinically cause a non-syndromic neurodevelopmental delay. In addition, we suggest that missense mutations affecting specific sites within zinc-finger domains might result in distinct and more severe clinical outcomes.

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“…The absence of functional BCL11B protein in mice blocks the T-cell lineage at the CD4 − CD8 − double-negative stage, affecting the differentiation and function of thymic lymphocytes (3). BCL11B also participates in the development of multiple systems, including neurogenesis of various neuronal subtypes (4), regeneration of epithelial cells (5), and formation of ameloblasts (6).…”

Section: Introductionmentioning

confidence: 99%

Mutant BCL11B in a Patient With a Neurodevelopmental Disorder and T-Cell Abnormalities

Yang

Kang

Hou³

et al. 2020

Front. Pediatr.

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Background: BCL11B encodes B-cell lymphoma/leukemia 11B, a transcription factor that participates in the differentiation and migration of neurons and lymphocyte cells. De novo mutations of BCL11B have been associated with neurodevelopmental disorder and immunodeficiency, such as immunodeficiency 49 (IMD49) and intellectual developmental disorder with speech delay, dysmorphic facies, and T-cell abnormalities (IDDSFTA). However, the pathogenesis of the neurodevelopmental disorder and T-cell deficiency is still mysterious. The strategy to distinguish these two diseases in detail is also unclear. Methods: A patient with unique clinical features was identified. Multiple examinations were applied for evaluation. Whole-exome sequencing (WES) and Sanger sequencing were also performed for the identification of the disease-causing mutation. Results: We reported a 17-month-old girl with intellectual disability, speech impairment, and delay in motor development. She presented with mild dysmorphic facial features and weak functional movement. MRI indicated the abnormal myelination of the white matter. Immunological analysis showed normal levels of RTEs and γδT cells but a deficiency of naive T cells. Genetic sequencing identified a de novo heterozygous frameshift mutation c.1192_1196delAGCCC in BCL11B. Conclusions: An IDDSFTA patient of East Asian origin was reported. The unreported neurological display, immunophenotype, and a novel disease-causing mutation of the patient extended the spectrum of clinical features and genotypes of IDDSFTA.

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Bcl11b—A Critical Neurodevelopmental Transcription Factor—Roles in Health and Disease

Cited by 54 publications

References 67 publications

Chromatin Remodeling BAF (SWI/SNF) Complexes in Neural Development and Disorders

Chromatin Remodeling BAF (SWI/SNF) Complexes in Neural Development and Disorders

BCL11B mutations in patients affected by a neurodevelopmental disorder with reduced type 2 innate lymphoid cells

Mutant BCL11B in a Patient With a Neurodevelopmental Disorder and T-Cell Abnormalities

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