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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Protein Data Bank
We thank all subjects and healthy donors for their support, and we thank H. Matthews and C. Neurwirth for coordinating control blood samples. This research was supported by the Intramural Research Programs of NIAMS, the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Clinical Center, and National Human Genome Research Institute, National Institutes of Health. This project was funded in whole or in part with federal funds from the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the US government. This work was supported by the Crohn's & Colitis Foundation of America (A.D.J.L. and H.H.U.), the US National Institutes of Health (grant KHL125593A to M.K.), the Sigrid Juselius and Emil Aaltonen Foundations (both to J.G.), the Wellcome Trust (grant 097261/Z/11/Z to B.A.; grant 105663/Z/14/Z to R.R.), the European Molecular Biology Organization (grant ALTF 11602012 to A.N.H.), a Marie Curie fellowship (FP7-PEOPLE-2012-IEF, proposal 330621, to A.N.H.), the Imperial College National Institute for Health Research (NIHR) Biomedical Research Centre (N.C. and P.K.), the Oxford NIHR Biomedical Research Centre (H.H.U.), the Chelsea & Westminster Hospital Charity (C.O'B.), the UK Biotechnology and Biological Sciences Research Council (BB/N0077941/1 to R.R. and M.F.S.), Cancer Research UK (C52623/A22597 to R.R.), the Westminster Medical School Research Trust (P.K.), the Biotechnology and Biological Sciences Research Council (grant BBS/E/B/000C0407 to M.A.L. and I.V.), the Cambridge Trust (I.V.), the Leona M. and Harry B. Helmsley Charitable Trust and ESPGHAN (H.H.U.), the MRC Clinical Sciences Centre (CSC) (T.J.A.) and the CSC Genomics Core Laboratory, and by MRC transition funding (T.J.A.). We acknowledge the contribution of the BRC Gastrointestinal biobank–Oxford IBD cohort study, which is supported by the NIHR Oxford Biomedical Research Centre. We thank G. Vahedi, E. Mathé, S. Parker, C. Kanellopoulou and S. Muljo for critical reading of the manuscript; J. Kabat for help with confocal image analysis; and S.S. De Ravin and H. Malech for advice on the use of MaxCyte. Molecular graphics and analyses were done with the UCSF Chimera package, developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco (supported by NIGMS P41-GM103311). This study used high-performance computational capabilities of Helix Systems at the NIH (http://helix.nih.gov).
Integrated supplementary information
Movie from confocal images of lymphocytes of a healthy donor. Green, BACH2; Blue, Hoechst stain.
Movie from confocal images of lymphocytes of BACH2E788K mutant patient. Green, BACH2; Blue, Hoechst stain.
Movies from confocal images of HEK293T cells transfected with Flag-tagged wild-type BACH2. Green, Flag; Blue, Hoechst stain
Movies from confocal images of HEK293T cells transfected with Flag-tagged BACH2E786K. Green, Flag; Blue, Hoechst stain.