BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency.
813 - 823
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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.
AuthorsAfzali, B; Grönholm, J; Vandrovcova, J; O'Brien, C; Sun, H-W; Vanderleyden, I; Davis, FP; Khoder, A; Zhang, Y; Hegazy, AN; Villarino, AV; Palmer, IW; Kaufman, J; Watts, NR; Kazemian, M; Kamenyeva, O; Keith, J; Sayed, A; Kasperaviciute, D; Mueller, M; Hughes, JD; Fuss, IJ; Sadiyah, MF; Montgomery-Recht, K; McElwee, J; Restifo, NP; Strober, W; Linterman, MA; Wingfield, PT; Uhlig, HH; Roychoudhuri, R; Aitman, TJ; Kelleher, P; Lenardo, MJ; O'Shea, JJ; Cooper, N; Laurence, ADJ
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