BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency

Nat Immunol. 2017 Jul;18(7):813-823. doi: 10.1038/ni.3753.

Behdad Afzali ¹ ², Juha Grönholm ³, Jana Vandrovcova ⁴ ⁵, Charlotte O'Brien ⁵, Hong-Wei Sun ¹, Ine Vanderleyden ⁶, Fred P Davis ¹, Ahmad Khoder ⁵, Yu Zhang ³, Ahmed N Hegazy ⁷ ⁸, Alejandro V Villarino ¹, Ira W Palmer ¹, Joshua Kaufman ¹, Norman R Watts ¹, Majid Kazemian ⁹, Olena Kamenyeva ³, Julia Keith ⁷, Anwar Sayed ⁵, Dalia Kasperaviciute ¹⁰, Michael Mueller ¹⁰, Jason D Hughes ¹¹, Ivan J Fuss ³, Mohammed F Sadiyah ⁶, Kim Montgomery-Recht ¹², Joshua McElwee ¹¹, Nicholas P Restifo ¹³, Warren Strober ³, Michelle A Linterman ⁶, Paul T Wingfield ¹, Holm H Uhlig ⁷ ¹⁴, Rahul Roychoudhuri ⁶, Timothy J Aitman ⁵ ¹⁵, Peter Kelleher ⁵, Michael J Lenardo ³, John J O'Shea ¹, Nichola Cooper ⁵, Arian D J Laurence ⁷ ¹⁶

Affiliations

1 Lymphocyte Cell Biology Section (Molecular Immunology and Inflammation Branch), Biodata Mining and Discovery Section and Protein Expression Laboratory, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA.
2 MRC Centre for Transplantation, King's College London, London, UK.
3 Molecular Development of the Immune System Section, NIAID Clinical Genomics Program, Biological Imaging Section (Research Technologies Branch) and Mucosal Immunity Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
4 Molecular Neuroscience, Institute of Neurology, Faculty of Brain Sciences, University College London, London, UK.
5 Department of Medicine, Imperial College London, London, UK.
6 Laboratory of Lymphocyte Signaling and Development, Babraham Institute, Cambridge, UK.
7 Translational Gastroenterology Unit, Nuffield Department of Medicine, John Radcliffe Hospital, Oxford, UK.
8 Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
9 Department of Biochemistry and Department of Computer Science, Purdue University, West Lafayette, Indiana, USA.
10 Imperial BRC Genomics Facility, Hammersmith Hospital, London, UK.
11 Merck Research Laboratories, Merck &Co. Inc., Boston, Massachusetts, USA.
12 Clinical Research Directorate/CMRP, Leidos Biomedical Research Inc., NCI at Frederick, Frederick, Maryland, USA.
13 National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
14 Department of Paediatrics, University of Oxford, Oxford, UK.
15 Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
16 Department of Haematology, Northern Centre for Cancer Care, Newcastle upon Tyne, UK.

PMID: 28530713 DOI: 10.1038/ni.3753

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.

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