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dc.contributor.authorAfzali, B
dc.contributor.authorGrönholm, J
dc.contributor.authorVandrovcova, J
dc.contributor.authorO'Brien, C
dc.contributor.authorSun, H-W
dc.contributor.authorVanderleyden, I
dc.contributor.authorDavis, FP
dc.contributor.authorKhoder, A
dc.contributor.authorZhang, Y
dc.contributor.authorHegazy, AN
dc.contributor.authorVillarino, AV
dc.contributor.authorPalmer, IW
dc.contributor.authorKaufman, J
dc.contributor.authorWatts, NR
dc.contributor.authorKazemian, M
dc.contributor.authorKamenyeva, O
dc.contributor.authorKeith, J
dc.contributor.authorSayed, A
dc.contributor.authorKasperaviciute, D
dc.contributor.authorMueller, M
dc.contributor.authorHughes, JD
dc.contributor.authorFuss, IJ
dc.contributor.authorSadiyah, MF
dc.contributor.authorMontgomery-Recht, K
dc.contributor.authorMcElwee, J
dc.contributor.authorRestifo, NP
dc.contributor.authorStrober, W
dc.contributor.authorLinterman, MA
dc.contributor.authorWingfield, PT
dc.contributor.authorUhlig, HH
dc.contributor.authorRoychoudhuri, R
dc.contributor.authorAitman, TJ
dc.contributor.authorKelleher, P
dc.contributor.authorLenardo, MJ
dc.contributor.authorO'Shea, JJ
dc.contributor.authorCooper, N
dc.contributor.authorLaurence, ADJ
dc.identifier.citationAfzali B, Grönholm J, Vandrovcova J, O'Brien C, Sun HW, Vanderleyden I, Davis FP, Khoder A, Zhang Y, Hegazy AN, Villarino AV, Palmer IW, Kaufman J, Watts NR, Kazemian M, Kamenyeva O, Keith J, Sayed A, Kasperaviciute D, Mueller M, Hughes JD, Fuss IJ, Sadiyah MF, Montgomery-Recht K, McElwee J, Restifo NP, Strober W, Linterman MA, Wingfield PT, Uhlig HH, Roychoudhuri R, Aitman TJ, Kelleher P, Lenardo MJ, O'Shea JJ, Cooper N, Laurence ADJ. BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency. Nat Immunol. 2017 Jul;18(7):813-823. doi: 10.1038/ni.3753. Epub 2017 May 22.en_US
dc.description.abstractThe transcriptional programs that guide lymphocyte differentiation depend on the precise expression and timing of transcription factors (TFs). The TF BACH2 is essential for T and B lymphocytes and is associated with an archetypal super-enhancer (SE). Single-nucleotide variants in the BACH2 locus are associated with several autoimmune diseases, but BACH2 mutations that cause Mendelian monogenic primary immunodeficiency have not previously been identified. Here we describe a syndrome of BACH2-related immunodeficiency and autoimmunity (BRIDA) that results from BACH2 haploinsufficiency. Affected subjects had lymphocyte-maturation defects that caused immunoglobulin deficiency and intestinal inflammation. The mutations disrupted protein stability by interfering with homodimerization or by causing aggregation. We observed analogous lymphocyte defects in Bach2-heterozygous mice. More generally, we observed that genes that cause monogenic haploinsufficient diseases were substantially enriched for TFs and SE architecture. These findings reveal a previously unrecognized feature of SE architecture in Mendelian diseases of immunity: heterozygous mutations in SE-regulated genes identified by whole-exome/genome sequencing may have greater significance than previously recognized.en_US
dc.description.sponsorshipThis research was supported by the Intramural Research Programs of NIAMS, the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Clinical Center, and National Human Genome Research Institute, National Institutes of Health. This project was funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001Een_US
dc.format.extent813 - 823
dc.publisherNature Publishing Groupen_US
dc.relation.ispartofNat Immunol
dc.subjectAdrenal Cortex Hormonesen_US
dc.subjectAutoimmune Diseasesen_US
dc.subjectBasic-Leucine Zipper Transcription Factorsen_US
dc.subjectImmunologic Deficiency Syndromesen_US
dc.subjectMiddle Ageden_US
dc.subjectPolymorphism, Single Nucleotideen_US
dc.subjectRespiratory Tract Infectionsen_US
dc.subjectTomography, X-Ray Computeden_US
dc.subjectYoung Adulten_US
dc.titleBACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency.en_US
pubs.organisational-group/Queen Mary University of London
pubs.organisational-group/Queen Mary University of London/Faculty of Medicine & Dentistry
pubs.organisational-group/Queen Mary University of London/Faculty of Medicine & Dentistry/William Harvey Research Institute
pubs.organisational-group/Queen Mary University of London/Faculty of Medicine & Dentistry/William Harvey Research Institute/Clinical Pharmacology

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