Common Variable Immunodeficiency Caused by FANC Mutations
Common Variable Immunodeficiency Caused by FANC Mutations
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DOI：
10.1007/s10875-017-0396-4
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发表时间：
2017-07-01
影响因子：
9.1
通讯作者：
Nonoyama, Shigeaki
中科院分区：
文献类型：
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作者：
Sekinaka, Yujin;Mitsuiki, Noriko;Nonoyama, Shigeaki
常见变异免疫缺陷（CVID）是由多种致病基因引起的最常见的成人发病的原发性抗体缺陷病。最近通过全外显子组测序 (WES) 分析，发现几种已知导致不同疾病的基因是导致患者 CVID 的原因。在这里，我们发现 FANC 基因突变是两名患者成人发病 CVID 的原因。 B细胞缺失，CD4(+) T细胞偏向CD45RO(+)记忆T细胞。两名患者均未检测到 T 细胞受体切除环 (TREC) 和信号接头 kappa 删除重组切除环 (sjKREC)。两名患者均未出现贫血、中性粒细胞减少或血小板减少症。使用 WES，我们在一名患者中鉴定出 FANCE 复合杂合突变，在另一名患者中鉴定出 FANCA 纯合突变。通过单泛素化测定和染色体脆性测试证实了 FANC 蛋白复合物的功能受损。然后，我们对 32 名范可尼贫血 (FA) 患者进行了多项免疫学评估，包括定量淋巴细胞分析和 TRECs/sjKRECs 分析。总共有 22 名 FA 患者（68.8%）被发现存在免疫学异常，表明此类免疫学发现在 FA 患者中可能很常见。这些数据表明，FANC 突变可能通过 DNA 复制应激的积累导致淋巴生成受损，从而导致 CVID。诊断 FA 非常重要，因为它极大地改变了临床管理。我们认为，FANC 突变除了导致骨髓衰竭和恶性肿瘤外，还可能导致孤立性免疫缺陷。
Common variable immunodeficiency (CVID) is the most common adult-onset primary antibody deficiency disease due to various causative genes. Several genes, which are known to be the cause of different diseases, have recently been reported as the cause of CVID in patients by performing whole exome sequencing (WES) analysis. Here, we found FANC gene mutations as a cause of adult-onset CVID in two patients. B cells were absent and CD4(+) T cells were skewed toward CD45RO(+) memory T cells. T-cell receptor excision circles (TRECs) and signal joint kappa-deleting recombination excision circles (sjKRECs) were undetectable in both patients. Both patients had no anemia, neutropenia, or thrombocytopenia. Using WES, we identified compound heterozygous mutations of FANCE in one patient and homozygous mutation of FANCA in another patient. The impaired function of FANC protein complex was confirmed by a monoubiquitination assay and by chromosome fragility test. We then performed several immunological evaluations including quantitative lymphocyte analysis and TRECs/sjKRECs analysis for 32 individuals with Fanconi anemia (FA). In total, 22 FA patients (68.8%) were found to have immunological abnormalities, suggesting that such immunological findings may be common in FA patients. These data indicate that FANC mutations are involved in impaired lymphogenesis probably by the accumulation of DNA replication stress, leading to CVID. It is important to diagnose FA because it drastically changes clinical management. We propose that FANC mutations can cause isolated immunodeficiency in addition to bone marrow failure and malignancy.