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

Página do item simplificado
dc.contributorSistema FMUSP-HC: Faculdade de Medicina da Universidade de São Paulo (FMUSP) e Hospital das Clínicas da FMUSP
dc.contributor.authorLESSEL, Davor
dc.contributor.authorGEHBAUER, Christina
dc.contributor.authorBRAMSWIG, Nuria C.
dc.contributor.authorSCHLUTH-BOLARD, Caroline
dc.contributor.authorVENKATARAMANAPPA, Sathish
dc.contributor.authorGASSEN, Koen L. I. van
dc.contributor.authorHEMPEL, Maja
dc.contributor.authorHAACK, Tobias B.
dc.contributor.authorBARESIC, Anja
dc.contributor.authorGENETTI, Casie A.
dc.contributor.authorFUNARI, Mariana F. A.
dc.contributor.authorLESSEL, Ivana
dc.contributor.authorKUHLMANN, Leonie
dc.contributor.authorSIMON, Ruth
dc.contributor.authorLIU, Pentao
dc.contributor.authorDENECKE, Jonas
dc.contributor.authorKUECHLER, Alma
dc.contributor.authorKRUIJFF, Ineke de
dc.contributor.authorSHOUKIER, Moneef
dc.contributor.authorLEK, Monkol
dc.contributor.authorMULLEN, Thomas
dc.contributor.authorLUEDECKE, Hermann-Josef
dc.contributor.authorLERARIO, Antonio M.
dc.contributor.authorKOBBE, Robin
dc.contributor.authorKRIEGER, Thorsten
dc.contributor.authorDEMEER, Benedicte
dc.contributor.authorLEBRUN, Marine
dc.contributor.authorKEREN, Boris
dc.contributor.authorNAVA, Caroline
dc.contributor.authorBURATTI, Julien
dc.contributor.authorAFENJAR, Alexandra
dc.contributor.authorSHINAWI, Marwan
dc.contributor.authorSACOTO, Maria J. Guillen
dc.contributor.authorGAUTHIER, Julie
dc.contributor.authorHAMDAN, Fadi F.
dc.contributor.authorLABERGE, Anne-Marie
dc.contributor.authorCAMPEAU, Philippe M.
dc.contributor.authorLOUIE, Raymond J.
dc.contributor.authorCATHEY, Sara S.
dc.contributor.authorPRINZ, Immo
dc.contributor.authorJORGE, Alexander A. L.
dc.contributor.authorTERHAL, Paulien A.
dc.contributor.authorLENHARD, Boris
dc.contributor.authorWIECZOREK, Dagmar
dc.contributor.authorSTROM, Tim M.
dc.contributor.authorAGRAWAL, Pankaj B.
dc.contributor.authorBRITSCH, Stefan
dc.contributor.authorTOLOSA, Eva
dc.contributor.authorKUBISCH, Christian
dc.date.accessioned2018-09-13T15:22:34Z
dc.date.available2018-09-13T15:22:34Z
dc.date.issued2018
dc.description.abstractThe 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.
dc.description.indexMEDLINE
dc.description.sponsorshipGerman Research Foundation [DFG TO-235, KFO296, DFG BR-2215]
dc.description.sponsorshipStudienstiftung des Deutschen Volkes
dc.description.sponsorshipGerman Ministry of Research and Education as part of the National Genome Research Network [01GS08167, 01GS08163]
dc.description.sponsorshipSao Paulo Research Foundation FAPESP [2013/03236-5, 2013/02162-8]
dc.description.sponsorshipNIH/NIAMS [1R01AR068429-01]
dc.description.sponsorshipNICHD/NHGRI/NIH [U19HD077671]
dc.description.sponsorshipFrench Ministry of Health (DGOS)
dc.description.sponsorshipFrench National Agency for Research (ANR) (PRTS 2013 grant)
dc.description.sponsorshipNational Institutes of Health [UM1 HG008900]
dc.identifier.citationBRAIN, v.141, p.2299-2311, 2018
dc.identifier.doi10.1093/brain/awy173
dc.identifier.eissn1460-2156
dc.identifier.issn0006-8950
dc.identifier.urihttps://observatorio.fm.usp.br/handle/OPI/28015
dc.language.isoeng
dc.publisherOXFORD UNIV PRESS
dc.relation.ispartofBrain
dc.rightsrestrictedAccess
dc.rights.holderCopyright OXFORD UNIV PRESS
dc.subjectBCL11B
dc.subjectdevelopmental delay
dc.subjectintellectual disability
dc.subjecttype 2 innate lymphoid cells
dc.subjectneurodevelopment
dc.subject.othertranscription factor bcl11b
dc.subject.otherintellectual disability
dc.subject.otherneuromedin u
dc.subject.otherinflammation
dc.subject.otherdifferentiation
dc.subject.otherhomeostasis
dc.subject.otherexpression
dc.subject.otherdisease
dc.subject.wosClinical Neurology
dc.subject.wosNeurosciences
dc.titleBCL11B mutations in patients affected by a neurodevelopmental disorder with reduced type 2 innate lymphoid cells
dc.typearticle
dc.type.categoryoriginal article
dc.type.versionpublishedVersion
dspace.entity.typePublication
hcfmusp.affiliation.countryInglaterra
hcfmusp.affiliation.countryAlemanha
hcfmusp.affiliation.countryEstados Unidos
hcfmusp.affiliation.countryCanadá
hcfmusp.affiliation.countryFrança
hcfmusp.affiliation.countryHolanda
hcfmusp.affiliation.countryisode
hcfmusp.affiliation.countryisofr
hcfmusp.affiliation.countryisonl
hcfmusp.affiliation.countryisogb
hcfmusp.affiliation.countryisous
hcfmusp.affiliation.countryisoca
hcfmusp.author.externalLESSEL, Davor:Univ Med Ctr Hamburg Eppendorf, Inst Human Genet, Martinistr 52, D-20246 Hamburg, Germany
hcfmusp.author.externalGEHBAUER, Christina:Univ Med Ctr Hamburg Eppendorf, Dept Immunol, Hamburg, Germany
hcfmusp.author.externalBRAMSWIG, Nuria C.:Univ Duisburg Essen, Univ Klinikum Essen, Inst Humangenet, Essen, Germany
hcfmusp.author.externalSCHLUTH-BOLARD, Caroline:Hosp Civils Lyon, Serv Genet, Lyon, France; UCBLyon1, CNRS, INSERM, Lyon Neurosc Res Ctr,GENDEV Team,U1028,UMR 5292, Bron, France
hcfmusp.author.externalVENKATARAMANAPPA, Sathish:Ulm Univ, Inst Mol & Cellular Anat, Ulm, Germany
hcfmusp.author.externalGASSEN, Koen L. I. van:Univ Med Ctr Utrecht, Dept Genet, Utrecht, Netherlands
hcfmusp.author.externalHEMPEL, Maja:Univ Med Ctr Hamburg Eppendorf, Inst Human Genet, Martinistr 52, D-20246 Hamburg, Germany
hcfmusp.author.externalHAACK, Tobias B.:Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany; Tech Univ Munich, Inst Human Genet, Munich, Germany; Univ Tubingen, Inst Med Genet & Appl Gen, Tubingen, Germany
hcfmusp.author.externalBARESIC, Anja:MRC London Inst Med Sci, Computat Regulatory Genom Grp, London, England
hcfmusp.author.externalGENETTI, Casie A.:Boston Childrens Hosp, Div Genet & Genom, Boston, MA USA; Boston Childrens Hosp, Div Newborn Med, Boston, MA USA; Harvard Med Sch, Boston, MA USA; Boston Childrens Hosp, Manton Ctr Orphan Dis Res, Boston, MA USA
hcfmusp.author.externalLESSEL, Ivana:Univ Med Ctr Hamburg Eppendorf, Inst Human Genet, Martinistr 52, D-20246 Hamburg, Germany
hcfmusp.author.externalKUHLMANN, Leonie:Hannover Med Sch, Inst Immunol, Hannover, Germany
hcfmusp.author.externalSIMON, Ruth:Ulm Univ, Inst Mol & Cellular Anat, Ulm, Germany
hcfmusp.author.externalLIU, Pentao:Wellcome Trust Sanger Inst, Cambridge, England
hcfmusp.author.externalDENECKE, Jonas:Univ Med Ctr Eppendorf, Dept Pediat, Hamburg, Germany
hcfmusp.author.externalKUECHLER, Alma:Univ Duisburg Essen, Univ Klinikum Essen, Inst Humangenet, Essen, Germany
hcfmusp.author.externalKRUIJFF, Ineke de:St Antonius Hosp, Dept Pediat, Nieuwegein, Netherlands
hcfmusp.author.externalSHOUKIER, Moneef:Pranatal Med Munchen, Munich, Germany
hcfmusp.author.externalLEK, Monkol:Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA; Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA
hcfmusp.author.externalMULLEN, Thomas:Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA 02114 USA; Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA 02142 USA
hcfmusp.author.externalLUEDECKE, Hermann-Josef:Univ Duisburg Essen, Univ Klinikum Essen, Inst Humangenet, Essen, Germany; Heinrich Heine Univ, Univ Clin, Inst Human Genet, Dusseldorf, Germany
hcfmusp.author.externalKOBBE, Robin:Univ Med Ctr Eppendorf, Dept Pediat, Hamburg, Germany
hcfmusp.author.externalKRIEGER, Thorsten:Univ Med Ctr Hamburg Eppendorf, Inst Clin Chem & Lab Med, Hamburg, Germany
hcfmusp.author.externalDEMEER, Benedicte:CHU Amiens Picardie, CLAD Nord France, Unite Genet Clin, Amiens, France
hcfmusp.author.externalLEBRUN, Marine:CHU Hop Nord, Serv Genet Clin Chromosom & Mol, St Etienne, France
hcfmusp.author.externalKEREN, Boris:Hop La Pitie Salpetriere, AP HP, Dept Genet, Paris, France
hcfmusp.author.externalNAVA, Caroline:Hop La Pitie Salpetriere, AP HP, Dept Genet, Paris, France
hcfmusp.author.externalBURATTI, Julien:Hop La Pitie Salpetriere, AP HP, Dept Genet, Paris, France
hcfmusp.author.externalAFENJAR, Alexandra: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
hcfmusp.author.externalSHINAWI, Marwan:Washington Univ, Sch Med, Dept Pediat, Div Genet & Genom Med, St Louis, MO 63110 USA
hcfmusp.author.externalSACOTO, Maria J. Guillen:GeneDx, Gaithersburg, MD USA
hcfmusp.author.externalGAUTHIER, Julie:CHU St Justine, Dept Pediat, Mol Diagnost Lab, Montreal, PQ, Canada; CHU St Justine, Dept Pediat, Div Med Genet, Montreal, PQ, Canada
hcfmusp.author.externalHAMDAN, Fadi F.:CHU St Justine, Dept Pediat, Mol Diagnost Lab, Montreal, PQ, Canada; CHU St Justine, Dept Pediat, Div Med Genet, Montreal, PQ, Canada
hcfmusp.author.externalLABERGE, Anne-Marie:Univ Montreal, CHU St Justine, Div Med Genet, Montreal, PQ, Canada; Univ Montreal, CHU St Justine, Res Ctr, Montreal, PQ, Canada; Univ Montreal, Dept Pediat, Montreal, PQ, Canada
hcfmusp.author.externalCAMPEAU, Philippe M.:CHU St Justine, Dept Pediat, Montreal, PQ, Canada; Univ Montreal, Montreal, PQ, Canada
hcfmusp.author.externalLOUIE, Raymond J.:Greenwood Genet Ctr, Greenwood, SC 29646 USA
hcfmusp.author.externalCATHEY, Sara S.:Greenwood Genet Ctr, Greenwood, SC 29646 USA
hcfmusp.author.externalPRINZ, Immo:Hannover Med Sch, Inst Immunol, Hannover, Germany
hcfmusp.author.externalTERHAL, Paulien A.:Univ Med Ctr Utrecht, Dept Genet, Utrecht, Netherlands
hcfmusp.author.externalLENHARD, Boris:MRC London Inst Med Sci, Computat Regulatory Genom Grp, London, England; Imperial Coll London, Inst Clin Sci, Fac Med, London, England
hcfmusp.author.externalWIECZOREK, Dagmar:Univ Duisburg Essen, Univ Klinikum Essen, Inst Humangenet, Essen, Germany; Heinrich Heine Univ, Univ Clin, Inst Human Genet, Dusseldorf, Germany
hcfmusp.author.externalSTROM, Tim M.:Helmholtz Zentrum Munchen, Inst Human Genet, Neuherberg, Germany; Tech Univ Munich, Inst Human Genet, Munich, Germany
hcfmusp.author.externalAGRAWAL, Pankaj B.:Boston Childrens Hosp, Div Genet & Genom, Boston, MA USA; Boston Childrens Hosp, Div Newborn Med, Boston, MA USA; Harvard Med Sch, Boston, MA USA; Boston Childrens Hosp, Manton Ctr Orphan Dis Res, Boston, MA USA
hcfmusp.author.externalBRITSCH, Stefan:Ulm Univ, Inst Mol & Cellular Anat, Ulm, Germany
hcfmusp.author.externalTOLOSA, Eva:Univ Med Ctr Hamburg Eppendorf, Dept Immunol, Hamburg, Germany
hcfmusp.author.externalKUBISCH, Christian:Univ Med Ctr Hamburg Eppendorf, Inst Human Genet, Martinistr 52, D-20246 Hamburg, Germany
hcfmusp.citation.scopus73
hcfmusp.contributor.author-fmusphcMARIANA FERREIRA DE ASSIS FUNARI
hcfmusp.contributor.author-fmusphcANTONIO MARCONDES LERARIO
hcfmusp.contributor.author-fmusphcALEXANDER AUGUSTO DE LIMA JORGE
hcfmusp.description.beginpage2299
hcfmusp.description.endpage2311
hcfmusp.description.volume141
hcfmusp.origemWOS
hcfmusp.origem.pubmed29985992
hcfmusp.origem.scopus2-s2.0-85055141566
hcfmusp.origem.wosWOS:000440991100019
hcfmusp.publisher.cityOXFORD
hcfmusp.publisher.countryENGLAND
hcfmusp.relation.referenceArlotta P, 2005, NEURON, V45, P207, DOI 10.1016/j.neuron.2004.12.036
hcfmusp.relation.referenceArlotta P, 2008, J NEUROSCI, V28, P622, DOI 10.1523/JNEUROSCI.2986-07.2008
hcfmusp.relation.referenceBasak A, 2015, J CLIN INVEST, V125, P2363, DOI 10.1172/JCI81163
hcfmusp.relation.referenceCalifano D, 2015, IMMUNITY, V43, P354, DOI 10.1016/j.immuni.2015.07.005
hcfmusp.relation.referenceCalifano D, 2014, J CLIN INVEST, V124, P174, DOI 10.1172/JCI70103
hcfmusp.relation.referenceCardoso V, 2017, NATURE, V549, P277, DOI 10.1038/nature23469
hcfmusp.relation.referenceChen K, 2009, NAT METHODS, V6, P677, DOI [10.1038/NMETH.1363, 10.1038/nmeth.1363]
hcfmusp.relation.referenceDazzo E, 2015, AM J HUM GENET, V96, P992, DOI 10.1016/j.ajhg.2015.04.020
hcfmusp.relation.referencede Bruin C, 2016, HORM RES PAEDIAT, V86, P342, DOI 10.1159/000446476
hcfmusp.relation.referenceDias C, 2016, AM J HUM GENET, V99, P253, DOI 10.1016/j.ajhg.2016.05.030
hcfmusp.relation.referenceGauthier J, 2018, ANN NEUROL, V83, P1089, DOI 10.1002/ana.25204
hcfmusp.relation.referenceGolonzhka O, 2009, J INVEST DERMATOL, V129, P1459, DOI 10.1038/jid.2008.392
hcfmusp.relation.referenceGolonzhka O, 2009, P NATL ACAD SCI USA, V106, P4278, DOI 10.1073/pnas.0900568106
hcfmusp.relation.referenceHamby Stephen E., 2011, Human Genomics, V5, P241
hcfmusp.relation.referenceHarmston N, 2017, NAT COMMUN, V8, DOI 10.1038/s41467-017-00524-5
hcfmusp.relation.referenceHempel M, 2015, AM J HUM GENET, V97, P493, DOI 10.1016/j.ajhg.2015.08.003
hcfmusp.relation.referenceIppolito GC, 2014, P NATL ACAD SCI USA, V111, pE998, DOI 10.1073/pnas.1319228111
hcfmusp.relation.referenceKlose CSN, 2017, NATURE, V549, P282, DOI 10.1038/nature23676
hcfmusp.relation.referenceKominami R, 2012, P JPN ACAD B-PHYS, V88, P72, DOI 10.2183/pjab.88.72
hcfmusp.relation.referenceKubo M, 2017, IMMUNOL REV, V278, P162, DOI 10.1111/imr.12557
hcfmusp.relation.referenceLek M, 2016, NATURE, V536, P285, DOI 10.1038/nature19057
hcfmusp.relation.referenceLennon MJ, 2017, FRONT CELL NEUROSCI, V11, DOI 10.3389/fncel.2017.00089
hcfmusp.relation.referenceLessel D, 2017, AM J HUM GENET, V101, P716, DOI 10.1016/j.ajhg.2017.09.014
hcfmusp.relation.referenceLi H, 2009, BIOINFORMATICS, V25, P1754, DOI 10.1093/bioinformatics/btp324
hcfmusp.relation.referenceLi L, 2013, BLOOD, V122, P902, DOI 10.1182/blood-2012-08-447839
hcfmusp.relation.referenceLi P, 2010, SCIENCE, V329, P85, DOI 10.1126/science.1188063
hcfmusp.relation.referenceLiu PT, 2003, NAT IMMUNOL, V4, P525, DOI 10.1038/ni925
hcfmusp.relation.referenceLivak KJ, 2001, METHODS, V25, P402, DOI 10.1006/meth.2001.1262
hcfmusp.relation.referenceLouie RJ, 2017, AM J MED GENET A, V173, P1219, DOI 10.1002/ajmg.a.38144
hcfmusp.relation.referenceMonticelli LA, 2011, NAT IMMUNOL, V12, P1045, DOI [10.1038/ni.2131, 10.1031/ni.2131]
hcfmusp.relation.referenceNajafabadi HS, 2015, NAT BIOTECHNOL, V33, P555, DOI 10.1038/nbt.3128
hcfmusp.relation.referencePetrovski S, 2013, PLOS GENET, V9, DOI 10.1371/journal.pgen.1003709
hcfmusp.relation.referencePunwani D, 2016, NEW ENGL J MED, V375, P2165, DOI 10.1056/NEJMoa1509164
hcfmusp.relation.referenceSamocha KE, 2014, NAT GENET, V46, P944, DOI 10.1038/ng.3050
hcfmusp.relation.referenceSimon R, 2016, GENES BRAIN BEHAV, V15, P405, DOI 10.1111/gbb.12287
hcfmusp.relation.referenceSimon R, 2012, EMBO J, V31, P2922, DOI 10.1038/emboj.2012.142
hcfmusp.relation.referenceSobreira Nara, 2015, Hum Mutat, V36, P928, DOI 10.1002/humu.22844
hcfmusp.relation.referenceTanaka AJ, 2015, AM J HUM GENET, V97, P457, DOI 10.1016/j.ajhg.2015.07.014
hcfmusp.relation.referenceThorvaldsdottir H, 2013, BRIEF BIOINFORM, V14, P178, DOI 10.1093/bib/bbs017
hcfmusp.relation.referencevan Rijt L, 2016, SEMIN IMMUNOPATHOL, V38, P483, DOI 10.1007/s00281-016-0556-2
hcfmusp.relation.referenceVenkataramanappa S, 2015, JOVE-J VIS EXP, DOI [10.3791/52550, DOI 10.3791/52550.]
hcfmusp.relation.referenceWakabayashi Y, 2003, NAT IMMUNOL, V4, P533, DOI 10.1038/ni927
hcfmusp.relation.referenceWalker JA, 2015, J EXP MED, V212, P875, DOI 10.1084/jem.20142224
hcfmusp.relation.referenceWallrapp A, 2017, NATURE, V549, P351, DOI 10.1038/nature24029
hcfmusp.relation.referenceWang ZX, 2012, PLOS ONE, V7, DOI 10.1371/journal.pone.0051262
hcfmusp.relation.referenceWolfe SA, 2000, ANNU REV BIOPH BIOM, V29, P183, DOI 10.1146/annurev.biophys.29.1.183
hcfmusp.relation.referenceYu Y, 2016, NATURE, V539, P102, DOI 10.1038/nature20105
hcfmusp.relation.referenceYu Y, 2015, J EXP MED, V212, P865, DOI 10.1084/jem.20142318
hcfmusp.scopus.lastupdate2024-05-10
relation.isAuthorOfPublicationff5fe88e-561d-4f18-98bf-93756c7670c6
relation.isAuthorOfPublication0e586d8e-f956-4b42-9e12-e6d5558cb290
relation.isAuthorOfPublication872493f0-3232-484e-a574-207e16fcf202
relation.isAuthorOfPublication.latestForDiscoveryff5fe88e-561d-4f18-98bf-93756c7670c6
Arquivos
Pacote Original
Agora exibindo 1 - 1 de 1
Nenhuma Miniatura disponível
Nome:
art_LESSEL_BCL11B_mutations_in_patients_affected_by_a_neurodevelopmental_2018.PDF
Tamanho:
1.15 MB
Formato:
Adobe Portable Document Format
Descrição:
publishedVersion (English)
Baixar
Coleções
Artigos e Materiais de Revistas Científicas - FM/MCM
Artigos e Materiais de Revistas Científicas - HC/ICHC
Artigos e Materiais de Revistas Científicas - LIM/25
Artigos e Materiais de Revistas Científicas - LIM/42
Artigos e Materiais de Revistas Científicas - ODS/03