دورية أكاديمية
BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency
| العنوان: | BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency |
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| المؤلفون: | Afzali, B, Grönholm, J, Vandrovcova, J, O'Brien, C, Sun, H, Vanderleyden, I, Davis, F, Khoder, A, Zhang, Y, Hegazy, A, Villarino, A, Palmer, I, Kaufman, J, Watts, N, Kazemian, M, Kamenyeva, O, Keith, J, Sayed, A, Kasperaviciute, D, Mueller, M, Hughes, J, Fuss, I, Sadiyah, M, Montgomery-Recht, K, McElwee, J, Restifo, N, Strober, W, Linterman, M, Wingfield, P, Uhlig, H, Roychoudhuri, R, Aitman, T, Kelleher, P, Lenardo, M, O'Shea, J, Cooper, N, Laurence, A |
| بيانات النشر: | Springer Nature |
| سنة النشر: | 2017 |
| المجموعة: | Oxford University Research Archive (ORA) |
| الوصف: | The 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. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| العلاقة: | https://ora.ox.ac.uk/objects/uuid:a4466ebb-6bde-468f-a25e-41b578db9f18Test; https://doi.org/10.1038/ni.3753Test |
| DOI: | 10.1038/ni.3753 |
| الإتاحة: | https://doi.org/10.1038/ni.3753Test https://ora.ox.ac.uk/objects/uuid:a4466ebb-6bde-468f-a25e-41b578db9f18Test |
| حقوق: | info:eu-repo/semantics/openAccess |
| رقم الانضمام: | edsbas.CB2FA17B |
| قاعدة البيانات: | BASE |
| DOI: | 10.1038/ni.3753 |
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