BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency.
Nat Immunol
; 18(7): 813-823, 2017 Jul.
Article
em En
| MEDLINE
| ID: mdl-28530713
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Doenças Autoimunes
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Fatores de Transcrição de Zíper de Leucina Básica
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Síndromes de Imunodeficiência
Tipo de estudo:
Prognostic_studies
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Risk_factors_studies
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article