BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency

Nature Immunology
Behdad AfzaliArian D J Laurence

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 sig...Continue Reading

References

Oct 16, 2004·Immunity·Makoto IwataSi-Young Song
Jun 10, 2006·Current Opinion in Rheumatology·Ulrich Salzer, Bodo Grimbacher
Jun 24, 2006·Journal of Cellular Biochemistry·Yasuhiro NakayamaSherman M Weissman
Oct 19, 2006·The Journal of Biological Chemistry·Kyoko OchiaiKazuhiko Igarashi
Jun 5, 2008·European Journal of Human Genetics : EJHG·Vinh T DangMark A Ragan
Jan 10, 2009·Nature Protocols·Da Wei HuangRichard A Lempicki
Mar 6, 2009·Genome Biology·Ben LangmeadSteven L Salzberg
May 20, 2009·Bioinformatics·Heng Li, Richard Durbin
Jul 3, 2009·International Archives of Allergy and Immunology·Sean DeaneM Eric Gershwin
Jan 1, 2010·The Journal of Allergy and Clinical Immunology·Luigi D Notarangelo
Jan 30, 2010·Bioinformatics·Aaron R Quinlan, Ira M Hall
Mar 2, 2010·Nature Genetics·Patrick C A DuboisDavid A van Heel
May 27, 2010·Scandinavian Journal of Immunology·G J ArasonB R Ludviksson
Jul 6, 2010·Nucleic Acids Research·Kai WangHakon Hakonarson
Oct 27, 2010·PLoS Genetics·Ni HuangMatthew E Hurles
Oct 29, 2010·Nature·Gonçalo R AbecasisGil A McVean
Nov 26, 2010·Proceedings of the National Academy of Sciences of the United States of America·Menno P CreyghtonRudolf Jaenisch
Aug 13, 2011·Nature·UNKNOWN International Multiple Sclerosis Genetics ConsortiumAlastair Compston
Sep 13, 2011·Lancet·Manuel A R FerreiraUNKNOWN Australian Asthma Genetics Consortium
Nov 15, 2011·Nucleic Acids Research·Hong-Mei ZhangAn-Yuan Guo
Dec 24, 2011·Acta Crystallographica. Section D, Biological Crystallography·Gareth O RosbrookStephanie C Wright
Nov 28, 2012·Cell·Golnaz VahediJohn J O'Shea
Jun 4, 2013·Nature·Rahul RoychoudhuriNicholas P Restifo
Jul 3, 2013·Frontiers in Immunology·Giovanni Antonio Maria PovoleriBehdad Afzali
Oct 15, 2013·Cell·Denes HniszRichard A Young
Oct 16, 2013·Proceedings of the National Academy of Sciences of the United States of America·Stephen C J ParkerUNKNOWN NISC Comparative Sequencing Program Authors
Apr 4, 2014·Nature Communications·Makoto KuwaharaMasakatsu Yamashita
Jun 3, 2014·Current Opinion in Immunology·Mary Ellen Conley, Jean-Laurent Casanova
Jul 25, 2014·Gastroenterology·Holm H UhligUNKNOWN COLORS in IBD Study Group and NEOPICS
Aug 16, 2014·Immunological Reviews·Kazuhiko IgarashiAkihiko Muto
Sep 27, 2014·Science·Frédéric Rieux-Laucat, Jean-Laurent Casanova
Feb 18, 2015·Nature·Golnaz VahediJohn J O'Shea

❮ Previous
Next ❯

Citations

Apr 21, 2018·Annual Review of Immunology·Holm H Uhlig, Fiona Powrie
Mar 15, 2018·ELife·Antoine GuérinJean-Laurent Casanova
Aug 26, 2018·Clinical and Experimental Immunology·A Hellesen, E Bratland
Oct 10, 2018·Current Opinion in Pediatrics·Joyce E YuYesim Yilmaz Demirdag
Nov 7, 2018·Nature Immunology·Giovanni A M PovoleriBehdad Afzali
May 14, 2018·Clinical Reviews in Allergy & Immunology·Stella HartonoNicholas L Rider
Sep 6, 2019·Current Rheumatology Reports·Helen LeavisRuth D E Fritsch-Stork
Jun 10, 2020·The Journal of Experimental Medicine·Francis M GrantRahul Roychoudhuri
Dec 1, 2018·The Journal of Experimental Medicine·Lucie RousselDonald C Vinh
Dec 12, 2019·Frontiers in Oncology·Manqing Wu, Jun Shen
Sep 15, 2020·Inflammation and Regeneration·Kaoru YamagataYoshiya Tanaka
Dec 5, 2019·Frontiers in Pediatrics·Shahrzad BakhtiarEleonora Gambineri
Jul 28, 2020·Nature Reviews. Gastroenterology & Hepatology·Matthew R KudelkaAndrew S Neish
Mar 21, 2019·Seminars in Immunopathology·Yuya HagiharaTakanori Kanai
Apr 10, 2019·Nature Genetics·Zachary L FullerMolly Przeworski
Oct 23, 2020·Experimental Dermatology·Rudolf StadlerRené Stranzenbach
Dec 18, 2020·Frontiers in Pediatrics·Magda Carneiro-SampaioAntonio Coutinho
Feb 4, 2021·Seminars in Immunopathology·Rosa Bacchetta, Kenneth Weinberg
Dec 6, 2020·Nature Reviews. Genetics·Andrew J KwokJulian C Knight
Feb 9, 2021·The Journal of Allergy and Clinical Immunology. in Practice·Roshini S Abraham, Manish J Butte
Apr 3, 2021·Cellular & Molecular Immunology·Georgios SogkasReinhold Ernst Schmidt
Apr 13, 2021·Frontiers in Immunology·Nilisha FernandoHan-Yu Shih
Apr 18, 2021·The Journal of Allergy and Clinical Immunology·Sarah K BaxterMary-Claire King
May 10, 2021·Endocrine·Marta FichnaMarek Ruchała
Jun 22, 2021·Current Opinion in Immunology·Neftali J RamirezBodo Grimbacher
May 20, 2021·Clinical and Experimental Immunology·Giorgio Costagliola, Rita Consolini
Jul 1, 2021·Nature Reviews. Rheumatology·Yuriy BaglaenkoSoumya Raychaudhuri

❮ Previous
Next ❯

Methods Mentioned

BETA
protein folding
exome sequencing
biopsy
flow cytometry
transgenic
density gradient centrifugation
ELISA
flow
Fluorescence
PMA

Software Mentioned

Adobe
CLC Main Workbench
UCSF Chimera
DataGraph
Annovar
PhyloP
Huygens
GATK
GraphPad Prism Pad
Polyphen2

Related Concepts

Related Feeds

Autoimmune Diseases

Autoimmune diseases occur as a result of an attack by the immune system on the body’s own tissues resulting in damage and dysfunction. There are different types of autoimmune diseases, in which there is a complex and unknown interaction between genetics and the environment. Discover the latest research on autoimmune diseases here.

CREs: Gene & Cell Therapy

Gene and cell therapy advances have shown promising outcomes for several diseases. The role of cis-regulatory elements (CREs) is crucial in the design of gene therapy vectors. Here is the latest research on CREs in gene and cell therapy.

Autoimmune Polyendocrinopathies

Autoimmune polyendocrinopathies, also called polyglandular autoimmune syndromes (PGASs), or polyendocrine autoimmune syndromes(PASs), are a heterogeneous group of rare diseases characterized by autoimmune activity against more than one endocrine organ, although non-endocrine organs can be affected. Discover the latest research on autoimmune polyendocrinopathies here.