BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency.
BACH2 immunodeficiency illustrates an association between super-enhancers and haploinsufficiency.
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DOI：
10.1038/ni.3753
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发表时间：
2017-07
影响因子：
30.5
通讯作者：
Laurence ADJ
中科院分区：
文献类型：
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作者：
Afzali B;Grönholm J;Vandrovcova J;O'Brien C;Sun HW;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
引导淋巴细胞分化的转录程序依赖于转录因子（TF）的精确表达和时机。BACH 2是T淋巴细胞和B淋巴细胞所必需的TF，并且与原型超级增强子（SE）相关。BACH 2基因座中的单核苷酸变异与多种自身免疫性疾病相关，但先前尚未鉴定出导致孟德尔单基因原发性免疫缺陷的BACH 2突变。我们描述了一个综合征BACH 2相关的免疫缺陷和自身免疫（BRIDA）造成的BACH 2单倍不足。患者有淋巴细胞成熟缺陷，导致免疫球蛋白缺乏和肠道炎症。这些突变通过干扰同源二聚化或引起聚集来破坏蛋白质的稳定性。Bach 2杂合子小鼠存在类似的淋巴细胞缺陷。更一般地说，我们发现引起单基因单倍体不足疾病的基因实质上富含TF和SE结构。这些观察结果显示了孟德尔免疫性疾病中SE结构的新特征，即在全外显子组/基因组测序中鉴定的SE调节基因中的杂合突变可能具有比公认的更大的意义。
Transcriptional programs guiding lymphocyte differentiation depend on precise expression and timing of transcription factors (TFs). BACH2 is a TF essential for T- and B-lymphocytes and is associated with an archetypal super-enhancer (SE). Single nucleotide variants in the BACH2 locus associate with multiple autoimmune diseases but BACH2 mutations causing Mendelian monogenic primary immunodeficiency have not previously been identified. We describe a syndrome of BACH2-related immunodeficiency and autoimmunity (BRIDA) resulting from BACH2 haploinsufficiency. Patients had lymphocyte maturation defects, causing immunoglobulin deficiency and intestinal inflammation. The mutations disrupted protein stability by interfering with homodimerization or by causing aggregation. Analogous lymphocyte defects existed in Bach2 heterozygous mice. More generally, we found that genes causing monogenic haploinsufficient diseases are substantially enriched for TFs and SE-architecture. These observations show a new feature of SE-architecture in Mendelian diseases of immunity, that heterozygous mutations in SE-regulated genes identified on whole exome/genome sequencing may have greater significance than recognized.
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影响因子：
16.6
作者：
Kuwahara, Makoto;Suzuki, Junpei;Tofukuji, Soichi;Yamada, Takeshi;Kanoh, Makoto;Matsumoto, Akira;Maruyama, Saho;Kometani, Kohei;Kurosaki, Tomohiro;Ohara, Osamu;Nakayama, Toshinori;Yamashita, Masakatsu
通讯作者：
Yamashita, Masakatsu
影响因子：
168.9
作者：
Ferreira, Manuel A. R.;Matheson, Melanie C.;Duffy, David L.;Marks, Guy B.;Hui, Jennie;Le Souef, Peter;Danoy, Patrick;Baltic, Svetlana;Nyholt, Dale R.;Jenkins, Mark;Hayden, Catherine;Willemsen, Gonneke;Ang, Wei;Kuokkanen, Mikko;Beilby, John;Cheah, Faang;de Geus, Eco J. C.;Ramasamy, Adaikalavan;Vedantam, Sailaja;Salomaa, Veikko;Madden, Pamela A.;Heath, Andrew C.;Hopper, John L.;Visscher, Peter M.;Musk, Bill;Leeder, Stephen R.;Jarvelin, Marjo-Riitta;Pennell, Craig;Boomsma, Dorret I.;Hirschhorn, Joel N.;Walters, Haydn;Martin, Nicholas G.;James, Alan;Jones, Graham;Abramson, Michael J.;Robertson, Colin F.;Dharmage, Shyamali C.;Brown, Matthew A.;Montgomery, Grant W.;Thompson, Philip J.
通讯作者：
Thompson, Philip J.
影响因子：
64.5
作者：
Hnisz D;Abraham BJ;Lee TI;Lau A;Saint-André V;Sigova AA;Hoke HA;Young RA
通讯作者：
Young RA
影响因子：
30.8
作者：
通讯作者：
--
DOI：
10.1182/asheducation-2012.1.301
发表时间：
2012-12-01
期刊：
HEMATOLOGY-AMERICAN SOCIETY HEMATOLOGY EDUCATION PROGRAM
影响因子：
--
作者：
Cunningham-Rundles, Charlotte
通讯作者：
Cunningham-Rundles, Charlotte