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, Behdad, Grönholm, Juha, Vandrovcova, Jana, O'Brien, Charlotte, Sun, Hong-Wei, Vanderleyden, Ine, Davis, Fred P, Khoder, Ahmad, Zhang, Yu, Hegazy, Ahmed N, Villarino, Alejandro V, Palmer, Ira W, Kaufman, Joshua, Watts, Norman R, Kazemian, Majid, Kamenyeva, Olena, Keith, Julia, Sayed, Anwar, Kasperaviciute, Dalia, Mueller, Michael, Hughes, Jason D, Fuss, Ivan J, Sadiyah, Mohammed F, Montgomery-Recht, Kim, McElwee, Joshua, Restifo, Nicholas P, Strober, Warren, Linterman, Michelle A, Wingfield, Paul T, Uhlig, Holm H, Roychoudhuri, Rahul, Aitman, Timothy J, Kelleher, Peter, Lenardo, Michael J, O'Shea, John J, Cooper, Nichola, Laurence, Arian DJ |
| بيانات النشر: | Springer Science and Business Media LLC //dx.doi.org/10.1038/ni.3753 Nat Immunol |
| سنة النشر: | 2017 |
| المجموعة: | Apollo - University of Cambridge Repository |
| مصطلحات موضوعية: | Adrenal Cortex Hormones, Adult, Autoimmune Diseases, Basic-Leucine Zipper Transcription Factors, Colitis, Female, Fever, Haploinsufficiency, Heterozygote, Humans, Immunologic Deficiency Syndromes, Lymphopenia, Male, Middle Aged, Mutation, Pancytopenia, Pedigree, Polymorphism, Single Nucleotide, Recurrence, Respiratory Tract Infections, Splenomegaly, Syndrome, Tomography, X-Ray Computed, Young Adult |
| 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 |
| وصف الملف: | application/pdf |
| اللغة: | English |
| العلاقة: | https://www.repository.cam.ac.uk/handle/1810/293962Test |
| DOI: | 10.17863/CAM.41070 |
| الإتاحة: | https://doi.org/10.17863/CAM.41070Test https://www.repository.cam.ac.uk/handle/1810/293962Test |
| حقوق: | All rights reserved |
| رقم الانضمام: | edsbas.B8455A76 |
| قاعدة البيانات: | BASE |
| DOI: | 10.17863/CAM.41070 |
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