Department of Hematology, Kanazawa University, Kanazawa, Japan.
Graduate School of Advanced Preventive Medical Sciences, Kanazawa University, Japan.
Haematologica. 2021 Jun 1;106(6):1581-1590. doi: 10.3324/haematol.2020.247809.
Leukocytes that lack HLA allelic expression are frequently detected in patients with acquired aplastic anemia (AA) who respond to immunosuppressive therapy (IST), although the exact mechanisms underlying the HLA loss and HLA allele repertoire likely to acquire loss-of-function mutations are unknown. We identified a common nonsense mutation at position 19 (c.19C>T, p.R7X) in exon 1 (Exon1mut) of different HLA-A and -B alleles in HLA-lacking granulocytes from AA patients. A droplet digital PCR (ddPCR) assay capable of detecting as few as 0.07% Exon1mut HLA alleles in total DNA revealed the mutation was present in 29% (101/353) of AA patients, with a median allele frequency of 0.42% (range, 0.071% to 21.3%). Exon1mut occurred in only 12 different HLA-A (n=4) and HLA-B (n=8) alleles, including B40:02 (n=31) and A02:06 (n=15), which correspond to 4 HLA supertypes (A02, A03, B07, and B44). The percentages of patients who possessed at least one of these 12 HLA alleles were significantly higher in the 353 AA patients (92%, P.
在对免疫抑制治疗 (IST) 有反应的获得性再生障碍性贫血 (AA) 患者中，经常检测到缺乏 HLA 等位基因表达的白细胞，尽管 HLA 丢失和可能获得失活功能突变的 HLA 等位基因库的确切机制尚不清楚。我们在 AA 患者缺乏粒细胞的不同 HLA-A 和 -B 等位基因的第 1 外显子 (Exon1mut) 中鉴定出一个常见的无义突变，位于第 19 位 (c.19C>T，p.R7X)。能够检测总 DNA 中低至 0.07% Exon1mut HLA 等位基因的液滴数字 PCR (ddPCR) 检测法显示，该突变存在于 29% (101/353) 的 AA 患者中，中位等位基因频率为 0.42% (范围为 0.071% 至 21.3%)。Exon1mut 仅发生在 12 个不同的 HLA-A (n=4) 和 HLA-B (n=8) 等位基因中，包括 B40:02 (n=31) 和 A02:06 (n=15)，它们对应于 4 个 HLA 超型 (A02、A03、B07 和 B44)。在 353 名 AA 患者中，至少携带这 12 个 HLA 等位基因之一的患者百分比显著更高 (92%，P<0.0001)。
