TY - JOUR
T1 - BCL11B mutations in patients affected by a neurodevelopmental disorder with reduced type 2 innate lymphoid cells
AU - Lessel, Davor
AU - Gehbauer, Christina
AU - Bramswig, Nuria C.
AU - Schluth-Bolard, Caroline
AU - Venkataramanappa, Sathish
AU - van Gassen, Koen L.I.
AU - Hempel, Maja
AU - Haack, Tobias B.
AU - Baresic, Anja
AU - Genetti, Casie A.
AU - Funari, Mariana F.A.
AU - Lessel, Ivana
AU - Kuhlmann, Leonie
AU - Simon, Ruth
AU - Liu, Pentao
AU - Denecke, Jonas
AU - Kuechler, Alma
AU - De Kruijff, Ineke
AU - Shoukier, Moneef
AU - Lek, Monkol
AU - Mullen, Thomas
AU - Lüdecke, Hermann Josef
AU - Lerario, Antonio M.
AU - Kobbe, Robin
AU - Krieger, Thorsten
AU - Demeer, Benedicte
AU - Lebrun, Marine
AU - Keren, Boris
AU - Nava, Caroline
AU - Buratti, Julien
AU - Afenjar, Alexandra
AU - Shinawi, Marwan
AU - Guillen Sacoto, Maria J.
AU - Gauthier, Julie
AU - Hamdan, Fadi F.
AU - Laberge, Anne Marie
AU - Campeau, Philippe M.
AU - Louie, Raymond J.
AU - Cathey, Sara S.
AU - Prinz, Immo
AU - Jorge, Alexander A.L.
AU - Terhal, Paulien A.
AU - Lenhard, Boris
AU - Wieczorek, Dagmar
AU - Strom, Tim M.
AU - Agrawal, Pankaj B.
AU - Britsch, Stefan
AU - Tolosa, Eva
AU - Kubisch, Christian
N1 - Funding Information:
This work was supported by the German Research Foundation DFG TO-235, KFO296 (to E.T.) and DFG BR-2215 (to S. Britsch), Studienstiftung des Deutschen Volkes (to C.G.), the German Ministry of Research and Education 01GS08167 (to D.W.) and 01GS08163 (to T.M.S.) as part of the National Genome Research Network, the São Paulo Research Foundation FAPESP 2013/03236–5 and 2013/02162-8 (to A.A.L.J.), by NIH/ NIAMS 1R01AR068429-01 and NICHD/NHGRI/NIH U19HD077671 (to P.B.A.l), and by the French Ministry of Health (DGOS) and the French National Agency for Research (ANR) (PRTS 2013 grant to C.S-B.). We thank the Broad Center for Mendelian Genomics for providing sequencing assistance in Family E, supported in part by National Institutes of Health UM1 HG008900 to D.M. and H.R.
Publisher Copyright:
© The Author(s) (2018). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.
PY - 2018/8/1
Y1 - 2018/8/1
N2 - 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.
AB - 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.
KW - BCL11B
KW - Developmental delay
KW - Intellectual disability
KW - Neurodevelopment
KW - Type 2 innate lymphoid cells
UR - http://www.scopus.com/inward/record.url?scp=85055141566&partnerID=8YFLogxK
U2 - 10.1093/brain/awy173
DO - 10.1093/brain/awy173
M3 - Article
C2 - 29985992
AN - SCOPUS:85055141566
VL - 141
SP - 2299
EP - 2311
JO - Brain
JF - Brain
SN - 0006-8950
IS - 8
ER -