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dc.contributor.authorAfzali, Behdaden
dc.contributor.authorGrönholm, Juhaen
dc.contributor.authorVandrovcova, Janaen
dc.contributor.authorO'Brien, Charlotteen
dc.contributor.authorSun, Hong-Weien
dc.contributor.authorVanderleyden, Ineen
dc.contributor.authorDavis, Fred Pen
dc.contributor.authorKhoder, Ahmaden
dc.contributor.authorZhang, Yuen
dc.contributor.authorHegazy, Ahmed Nen
dc.contributor.authorVillarino, Alejandro Ven
dc.contributor.authorPalmer, Ira Wen
dc.contributor.authorKaufman, Joshuaen
dc.contributor.authorWatts, Norman Ren
dc.contributor.authorKazemian, Majiden
dc.contributor.authorKamenyeva, Olenaen
dc.contributor.authorKeith, Juliaen
dc.contributor.authorSayed, Anwaren
dc.contributor.authorKasperaviciute, Daliaen
dc.contributor.authorMueller, Michaelen
dc.contributor.authorHughes, Jason Den
dc.contributor.authorFuss, Ivan Jen
dc.contributor.authorSadiyah, Mohammed Fen
dc.contributor.authorMontgomery-Recht, Kimen
dc.contributor.authorMcElwee, Joshuaen
dc.contributor.authorRestifo, Nicholas Pen
dc.contributor.authorStrober, Warrenen
dc.contributor.authorLinterman, Michelleen
dc.contributor.authorWingfield, Paul Ten
dc.contributor.authorUhlig, Holm Hen
dc.contributor.authorRoychoudhuri, Rahulen
dc.contributor.authorAitman, Timothy Jen
dc.contributor.authorKelleher, Peteren
dc.contributor.authorLenardo, Michael Jen
dc.contributor.authorO'Shea, John Jen
dc.contributor.authorCooper, Nicholaen
dc.contributor.authorLaurence, Arian DJen
dc.date.accessioned2019-06-24T23:31:55Z
dc.date.available2019-06-24T23:31:55Z
dc.date.issued2017-07-01en
dc.identifier.issn1529-2908
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/293962
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.
dc.languageengen
dc.rightsAll rights reserved
dc.rights.uri
dc.titleBACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency.en
dc.typeArticle
prism.issueIdentifier7en
prism.publicationDate2017en
prism.publicationNameNat Immunolen
prism.volume18en
dc.identifier.doi10.17863/CAM.41070
dcterms.dateAccepted2017-04-25en
rioxxterms.versionofrecord10.1038/ni.3753en
rioxxterms.versionAM
rioxxterms.licenseref.urihttp://www.rioxx.net/licenses/all-rights-reserveden
rioxxterms.licenseref.startdate2017-07-01en
dc.contributor.orcidZhang, Yu [0000-0002-6904-0372]
dc.contributor.orcidVillarino, Alejandro V [0000-0001-8068-2176]
dc.contributor.orcidLinterman, Michelle [0000-0001-6047-1996]
dc.contributor.orcidRoychoudhuri, Rahul [0000-0002-5392-1853]
dc.identifier.eissn1529-2916
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idWellcome Trust (105663/Z/14/Z)
cam.issuedOnline2017-05-27en
rioxxterms.freetoread.startdate2018-01-31


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