BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency
File(s)
Accepted version
Supporting information
Author(s)
Type
Journal Article
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.
Date Issued
2017-07-01
Date Acceptance
2017-04-25
Citation
Nature Immunology, 2017, 18 (7), pp.813-+
ISSN
1529-2908
Publisher
Nature Publishing Group
Start Page
813
End Page
+
Journal / Book Title
Nature Immunology
Volume
18
Issue
7
Copyright Statement
© 2017 Nature America, Inc., part of Springer Nautre. All rights reserved.
Sponsor
Westminster Medical School Research Trust
Westminster Medical School Research Trust
Imperial College Healthcare NHS Trust- BRC Funding
Leuka
Imperial College Healthcare NHS Trust- BRC Funding
Imperial College Healthcare NHS Trust- BRC Funding
Imperial College Healthcare NHS Trust- BRC Funding
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000403676300016&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Grant Number
JRC PhD 001 03/13-14
PMS/MMS-12/13-4152(IMM 2)
RDF01
N/A
RDB05 79560
RD610 79560
RDB05 79560
Subjects
Science & Technology
Life Sciences & Biomedicine
Immunology
COMMON VARIABLE IMMUNODEFICIENCY
PLASMA-CELL-DIFFERENTIATION
GENOME-WIDE ASSOCIATION
T-CELLS
B-CELLS
FUNCTIONAL PREDICTIONS
TRANSCRIPTION FACTORS
SUSCEPTIBILITY LOCI
SEQUENCING DATA
RISK LOCI
Publication Status
Published
Date Publish Online
2017-05-22