1. BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency
- Author
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Mohammed F Sadiyah, Ira Palmer, Anwar A. Sayed, Ahmad Khoder, Joshua Kaufman, Warren Strober, Alejandro V. Villarino, Paul T. Wingfield, Michael Mueller, Majid Kazemian, Joshua McElwee, Ahmed N. Hegazy, Behdad Afzali, Fred P. Davis, Julia Keith, Jason D. Hughes, Hong-Wei Sun, Charlotte O'Brien, Holm H. Uhlig, Michelle A. Linterman, Yu Zhang, Arian Laurence, Nichola Cooper, John J. O'Shea, Ine Vanderleyden, Dalia Kasperaviciute, Timothy J. Aitman, Rahul Roychoudhuri, Olena Kamenyeva, Juha Grönholm, Kim Montgomery-Recht, Ivan J. Fuss, Nicholas P. Restifo, Norman R. Watts, Peter Kelleher, Jana Vandrovcova, Michael J. Lenardo, Westminster Medical School Research Trust, Imperial College Healthcare NHS Trust- BRC Funding, Leuka, Zhang, Yu [0000-0002-6904-0372], Villarino, Alejandro V [0000-0001-8068-2176], Roychoudhuri, Rahul [0000-0002-5392-1853], and Apollo - University of Cambridge Repository
- Subjects
0301 basic medicine ,Male ,Pancytopenia ,AUTOIMMUNITY ,Genome-wide association study ,CELL DIFFERENTIATION ,Haploinsufficiency ,Adrenal Cortex Hormones ,Recurrence ,Plasma cell differentiation ,Immunology and Allergy ,Respiratory Tract Infections ,Immunodeficiency ,Genetics ,Lymphocyte differentiation ,Syndrome ,Middle Aged ,Colitis ,3. Good health ,Pedigree ,TRANSCRIPTION FACTORS ,Basic-Leucine Zipper Transcription Factors ,PLASMA-CELL-DIFFERENTIATION ,1107 Immunology ,B-CELLS ,Female ,FUNCTIONAL PREDICTIONS ,Life Sciences & Biomedicine ,Adult ,Heterozygote ,SUSCEPTIBILITY LOCI ,SEQUENCING DATA ,Fever ,DATABASE ,Immunology ,COMMON VARIABLE IMMUNODEFICIENCY ,Polymorphism, Single Nucleotide ,Article ,CLASSIFICATION ,Autoimmune Diseases ,03 medical and health sciences ,Young Adult ,Lymphopenia ,Journal Article ,medicine ,Humans ,GENOME-WIDE ASSOCIATION ,Gene ,METAANALYSIS ,Science & Technology ,IDENTIFICATION ,business.industry ,Common variable immunodeficiency ,Immunologic Deficiency Syndromes ,medicine.disease ,RISK LOCI ,030104 developmental biology ,Mutation ,Splenomegaly ,Primary immunodeficiency ,T-CELLS ,business ,Tomography, X-Ray Computed - Abstract
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.
- Published
- 2017
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