Recurrent microdeletions at chromosome 2p11.2 are associated with thymic hypoplasia and features resembling DiGeorge syndrome
Recurrent microdeletions at chromosome 2p11.2 are associated with thymic hypoplasia and features resembling DiGeorge syndrome
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DOI：
10.1016/j.jaci.2019.09.020
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发表时间：
2020-01-01
影响因子：
14.2
通讯作者：
Atkinson, T. Prescott
中科院分区：
文献类型：
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作者：
Bernstock, Joshua D.;Totten, Arthur H.;Atkinson, T. Prescott
背景资料：胸腺发育不全/再生障碍性贫血发生的一部分，DiGeorge综合征，有几个已知的遗传原因，并失去了功能的突变叉头框N1（FOXN 1）。目的：我们试图确定的原因，选择性T细胞淋巴细胞减少症与倒置的kappa/lambda比率在几个kindrix.Methods：患者通过新生儿筛选确定严重的联合免疫缺陷使用T细胞受体切除环试验。那些发现有选择性T细胞淋巴细胞减少症的人接受了染色体微阵列分析的测试。将叉头框I3（FOXI 3）缺失功能突变的三周龄杂合子小鼠与野生型同窝小鼠进行比较，FOXI 3是在患者中发现的常见缺失区域内的候选基因。评估包括体重和器官重量，流式细胞术分析的胸腺细胞和脾细胞，胸腺tissue.Results的组织学/transcriptomic分析：5 kinatomy具有相似的免疫表型，包括选择性T细胞淋巴细胞减少症重叠微缺失染色体2p11.2跨越FOXI 3，在大多数情况下，免疫球蛋白κ轻链位点。在FOXI 3基因敲除小鼠品系中的研究显示，与野生型动物相比，杂合子动物的体重更小，胸腺重量相对更低。组织学和流式细胞术对3周龄幼仔脾脏和胸腺的T细胞和B细胞亚群以及上皮细胞没有显示出任何显著的定性或定量差异。胸腺RNA的转录组学分析揭示了全球转录组学特征的差异，并且Inflamity Pathway分析揭示了上皮粘附连接的预测功能障碍。染色体2p11.2的微缺失与人类受试者的T细胞淋巴细胞减少症和可能的胸腺发育不全相关，缺失区域内的候选基因FOXI 3的单倍不足是可能的潜在原因。
Background: Thymic hypoplasia/aplasia occurs as a part of DiGeorge syndrome, which has several known genetic causes, and with loss-of-function mutations in forkhead box N1 (FOXN1).Objective: We sought to determine the cause of selective T-cell lymphopenia with inverted kappa/lambda ratio in several kindreds.Methods: Patients were identified through newborn screening for severe combined immunodeficiency using the T-cell receptor excision circle assay. Those found to have selective T-cell lymphopenia underwent testing with chromosomal microarray analysis. Three-week-old mice heterozygous for a loss-offunction mutation in forkhead box I3 (FOXI3), a candidate gene within the common deleted region found in patients, were compared with wild-type littermates. Assessments included body and organ weights, flow cytometric analysis of thymocytes and splenocytes, and histologic/transcriptomic analyses of thymic tissue.Results: Five kindreds with similar immunophenotypes that included selective T-cell lymphopenia had overlapping microdeletions at chromosome 2p11.2 that spanned FOXI3 and, in most cases, the immunoglobulin kappa light chain locus. Studies in a mouse knockout strain for FOXI3 revealed smaller body weights and relatively lower thymus weights in heterozygous compared with wild-type animals. Histology and flow cytometry on spleens and thymi from 3-week-old pups for T- and B-cell subsets and epithelial cells did not show any significant qualitative or quantitative differences.Transcriptomic analysis of thymic RNA revealed divergence in global transcriptomic signatures, and Ingenuity Pathway Analysis revealed predicted dysfunction in epithelial adherens junctions.Conclusions: Microdeletions at chromosome 2p11.2 are associated with T-cell lymphopenia and probable thymic hypoplasia in human subjects, and haploinsufficiency for FOXI3, a candidate gene within the deleted region, is the likely underlying cause.