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BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency.

Afzali, Behdad; Grönholm, Juha; Vandrovcova, Jana; O'Brien, Charlotte; Sun, Hong-Wei; Vanderleyden, Ine; Davis, Fred P; Khoder, Ahmad; Zhang, Yu; Hegazy, Ahmed N; Villarino, Alejandro V; Palmer, Ira W; Kaufman, Joshua; Watts, Norman R; Kazemian, Majid; Kamenyeva, Olena; Keith, Julia; Sayed, Anwar; Kasperaviciute, Dalia; Mueller, Michael; Hughes, Jason D; Fuss, Ivan J; Sadiyah, Mohammed F; Montgomery-Recht, Kim; McElwee, Joshua; Restifo, Nicholas P; Strober, Warren; Linterman, Michelle A; Wingfield, Paul T; Uhlig, Holm H; Roychoudhuri, Rahul; Aitman, Timothy J; Kelleher, Peter; Lenardo, Michael J; O'Shea, John J; Cooper, Nichola; Laurence, Arian D J.
Nat Immunol; 18(7): 813-823, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28530713
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.
Selo DaSilva