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

Brain 2018 08;141(8):2299-2311

Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

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.

Download full-text PDF

http://dx.doi.org/10.1093/brain/awy173DOI Listing
August 2018
69 Reads
9.200 Impact Factor

Publication Analysis

Top Keywords

missense mutation
type innate
immune deficiency
lymphoid cells
innate lymphoid
role bcl11b
bcl11b-deficient mice
immune system
located premature
premature termination
patient c-terminally
structural interface
dna-binding structural
interface published
published patient
termination codon
c-terminally located


(Supplied by CrossRef)
Neuronal subtype-specific genes that control corticospinal motor neuron development in vivo
Arlotta et al.
Neuron 2005
Ctip2 controls the differentiation of medium spiny neurons and the establishment of the cellular architecture of the striatum
Arlotta et al.
J Neurosci 2008
BCL11A deletions result in fetal hemoglobin persistence and neurodevelopmental alterations
Basak et al.
J Clin Invest 2015
Transcription factor Bcl11b controls identity and function of mature type 2 innate lymphoid cells
Califano et al.
Immunity 2015
Diverting T helper cell trafficking through increased plasticity attenuates autoimmune encephalomyelitis
Califano et al.
J Clin Invest 2014
Neuronal regulation of type 2 innate lymphoid cells via neuromedin U
Cardoso et al.
Nature 2017
BreakDancer: an algorithm for high-resolution mapping of genomic structural variation
Chen et al.
Nat Methods 2009
Heterozygous reelin mutations cause autosomal-dominant lateral temporal epilepsy
Dazzo et al.
Am J Hum Genet 2015
Two patients with severe short stature due to a FBN1 mutation (p.Ala1728Val) with a mild form of acromicric dysplasia
de Bruin et al.
Horm Res Paediatr 2016
BCL11A haploinsufficiency causes an intellectual disability syndrome and dysregulates transcription
Dias et al.
Am J Hum Genet 2016
Recessive mutations in VPS13D cause childhood-onset movement disorders
Gauthier et al.
Ann Neurol 2018

Similar Publications