Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Ala.
National Human Genome Research Institute, National Institutes of Health, Bethesda, Md.
J Allergy Clin Immunol. 2020 Jan;145(1):358-367.e2. doi: 10.1016/j.jaci.2019.09.020. Epub 2019 Oct 7.
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).
We sought to determine the cause of selective T-cell lymphopenia with inverted kappa/lambda ratio in several kindreds.
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-of-function 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.
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.
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.
胸腺瘤/发育不良是 DiGeorge 综合征的一部分，该综合征有几个已知的遗传原因，并且存在叉头框 N1（FOXN1）的功能丧失突变。
我们试图确定几个家族中具有倒置κ/λ比的选择性 T 细胞淋巴细胞减少症的原因。
通过使用 T 细胞受体切除环测定法对严重联合免疫缺陷症进行新生儿筛查来鉴定患者。发现具有选择性 T 细胞淋巴细胞减少症的患者接受了染色体微阵列分析测试。与野生型同窝仔相比，比较了 3 周龄杂合子叉头框 I3（FOXI3）功能丧失突变的小鼠，FOXI3 是患者中常见缺失区域的候选基因。评估包括体重和器官重量，胸腺细胞和脾细胞的流式细胞术分析以及胸腺组织的组织学/转录组学分析。
五个具有相似免疫表型的家族，包括选择性 T 细胞淋巴细胞减少症，在染色体 2p11.2 上具有重叠的微缺失，这些缺失跨越了 FOXI3，并且在大多数情况下跨越了免疫球蛋白κ轻链基因座。在 FOXI3 敲除小鼠品系中的研究表明，杂合子动物的体重和相对较低的胸腺重量均低于野生型动物。来自 3 周龄幼仔的脾脏和胸腺的 T 和 B 细胞亚群和上皮细胞的组织学和流式细胞术未显示任何明显的定性或定量差异。胸腺 RNA 的转录组分析显示出全局转录组特征的差异，并且Ingenuity 途径分析显示上皮细胞黏附连接的预测功能障碍。
染色体 2p11.2 上的微缺失与人类 T 细胞淋巴细胞减少症和可能的胸腺发育不良有关，并且缺失区域内的候选基因 FOXI3 的杂合不足可能是潜在的原因。
