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

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Autor(es):
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Lessel, Davor [1] ; Gehbauer, Christina [2] ; Bramswig, Nuria C. [3] ; Schluth-Bolard, Caroline [4, 5] ; Venkataramanappa, Sathish [6] ; van Gassen, Koen L. I. [7] ; Hempel, Maja [1] ; Haack, Tobias B. [8, 9, 10] ; Baresic, Anja [11] ; Genetti, Casie A. [12, 13, 14, 15] ; Funari, Mariana F. A. [16] ; Lessel, Ivana [1] ; Kuhlmann, Leonie [17] ; Simon, Ruth [6] ; Liu, Pentao [18] ; Denecke, Jonas [19] ; Kuechler, Alma [3] ; de Kruijff, Ineke [20] ; Shoukier, Moneef [21] ; Lek, Monkol [22, 23] ; Mullen, Thomas [22, 23] ; Luedecke, Hermann-Josef [3, 24] ; Lerario, Antonio M. [25, 26] ; Kobbe, Robin [19] ; Krieger, Thorsten [27] ; Demeer, Benedicte [28] ; Lebrun, Marine [29] ; Keren, Boris [30] ; Nava, Caroline [30] ; Buratti, Julien [30] ; Afenjar, Alexandra [31] ; Shinawi, Marwan [32] ; Sacoto, Maria J. Guillen [33] ; Gauthier, Julie [34, 35] ; Hamdan, Fadi F. [34, 35] ; Laberge, Anne-Marie [36, 37, 38] ; Campeau, Philippe M. [39, 40] ; Louie, Raymond J. [41] ; Cathey, Sara S. [41] ; Prinz, Immo [17] ; Jorge, Alexander A. L. [25, 16] ; Terhal, Paulien A. [7] ; Lenhard, Boris [11, 42] ; Wieczorek, Dagmar [3, 24] ; Strom, Tim M. [8, 9] ; Agrawal, Pankaj B. [12, 13, 14, 15] ; Britsch, Stefan [6] ; Tolosa, Eva [2] ; Kubisch, Christian [1]
Número total de Autores: 49
Afiliação do(s) autor(es):
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[1] Univ Med Ctr Hamburg Eppendorf, Inst Human Genet, Martinistr 52, D-20246 Hamburg - Germany
[2] Univ Med Ctr Hamburg Eppendorf, Dept Immunol, Hamburg - Germany
[3] Univ Duisburg Essen, Univ Klinikum Essen, Inst Humangenet, Essen - Germany
[4] Hosp Civils Lyon, Serv Genet, Lyon - France
[5] UCBLyon1, CNRS, INSERM, Lyon Neurosc Res Ctr, GENDEV Team, U1028, UMR 5292, Bron - France
[6] Ulm Univ, Inst Mol & Cellular Anat, Ulm - Germany
[7] Univ Med Ctr Utrecht, Dept Genet, Utrecht - Netherlands
[8] Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg - Germany
[9] Tech Univ Munich, Inst Human Genet, Munich - Germany
[10] Univ Tubingen, Inst Med Genet & Appl Gen, Tubingen - Germany
[11] MRC London Inst Med Sci, Computat Regulatory Genom Grp, London - England
[12] Harvard Med Sch, Boston, MA - USA
[13] Boston Childrens Hosp, Div Genet & Genom, Boston, MA - USA
[14] Boston Childrens Hosp, Div Newborn Med, Boston, MA - USA
[15] Boston Childrens Hosp, Manton Ctr Orphan Dis Res, Boston, MA - USA
[16] Univ Sao Paulo, Fac Med, Lab Hormonios Genet Mol LIM42, Hosp Clin, Unidade Endocrinol Desenvolvimento, Sao Paulo - Brazil
[17] Hannover Med Sch, Inst Immunol, Hannover - Germany
[18] Wellcome Trust Sanger Inst, Cambridge - England
[19] Univ Med Ctr Eppendorf, Dept Pediat, Hamburg - Germany
[20] St Antonius Hosp, Dept Pediat, Nieuwegein - Netherlands
[21] Pranatal Med Munchen, Munich - Germany
[22] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 - USA
[23] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 - USA
[24] Heinrich Heine Univ, Univ Clin, Inst Human Genet, Dusseldorf - Germany
[25] Univ Michigan, Dept Internal Med, Div Metab Endocrinol & Diabet, Ann Arbor, MI 48109 - USA
[26] Univ Sao Paulo, Fac Med, Hosp Clin, Unidade Endocrinol Genet LIM25, Sao Paulo - Brazil
[27] Univ Med Ctr Hamburg Eppendorf, Inst Clin Chem & Lab Med, Hamburg - Germany
[28] CHU Amiens Picardie, CLAD Nord France, Unite Genet Clin, Amiens - France
[29] CHU Hop Nord, Serv Genet Clin Chromosom & Mol, St Etienne - France
[30] Hop La Pitie Salpetriere, AP HP, Dept Genet, Paris - France
[31] Sorbonne Univ, Hop Armand Trousseau, Dept Genet Med, AP HP, GRC 19 Pathol Congenitales Cervelet LeucoDy, Ctr Reference Deficiences Intellectuelles Causes, F-75012 Paris - France
[32] Washington Univ, Sch Med, Dept Pediat, Div Genet & Genom Med, St Louis, MO 63110 - USA
[33] GeneDx, Gaithersburg, MD - USA
[34] CHU St Justine, Dept Pediat, Mol Diagnost Lab, Montreal, PQ - Canada
[35] CHU St Justine, Dept Pediat, Div Med Genet, Montreal, PQ - Canada
[36] Univ Montreal, CHU St Justine, Div Med Genet, Montreal, PQ - Canada
[37] Univ Montreal, CHU St Justine, Res Ctr, Montreal, PQ - Canada
[38] Univ Montreal, Dept Pediat, Montreal, PQ - Canada
[39] Univ Montreal, Montreal, PQ - Canada
[40] CHU St Justine, Dept Pediat, Montreal, PQ - Canada
[41] Greenwood Genet Ctr, Greenwood, SC 29646 - USA
[42] Imperial Coll London, Inst Clin Sci, Fac Med, London - England
Número total de Afiliações: 42
Tipo de documento: Artigo Científico
Fonte: BRAIN; v. 141, n. 8, p. 2299-2311, AUG 2018.
Citações Web of Science: 6
Resumo

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. (AU)

Processo FAPESP: 13/03236-5 - Novas abordagens e metodologias na investigação genético-molecular dos distúrbios de crescimento e desenvolvimento puberal
Beneficiário:Alexander Augusto de Lima Jorge
Linha de fomento: Auxílio à Pesquisa - Temático
Processo FAPESP: 13/02162-8 - Patogênese molecular e caracterização de doenças monogênicas do desenvolvimento: um caminho para a medicina translacional
Beneficiário:Berenice Bilharinho de Mendonça
Linha de fomento: Auxílio à Pesquisa - Temático