一例网状发育不全并同时患有B细胞急性淋巴细胞白血病的患者中由纯合AK2 c.498+1G>A变异导致的异常剪接
Aberrant splicing caused by a homozygous AK2 c.498 + 1G > A variant in a patient with reticular dysgenesis and concurrent B-cell acute lymphoblastic leukemia.
文献信息
| PMID | 42874964 |
|---|---|
| 原文 | 在 PubMed 查看原文 ↗ |
| 发表日期 | 2026 |
| 作者 | Longkai He |
| 作者单位 | Division of Neonatology and Center for Newborn Care, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, China. |
| 期刊 | Gene |
| SCI 分区 | Q2 |
| IF | 2.9 |
| 研究类型 | 基础研究 · 基础／转化 |
| 所属专科 | 耳科 |
中文摘要
背景： 网状发育不全（RD）是一种罕见的常染色体隐性遗传性重症联合免疫缺陷，以严重中性粒细胞减少、T细胞淋巴细胞减少和感音神经性听力损失为特征，由AK2双等位基因功能丧失变异引起。方法：我们在一名患有RD并同时患有B细胞急性淋巴细胞白血病（B-ALL）的男孩中鉴定出一个纯合AK2剪接位点变异（c.498+1G>A），这种临床组合此前未在与AK2变异相关的情况下被报道。结果：体外微小基因试验显示，c.498+1G>A破坏了经典5'剪接供体位点，并产生一个在外显子5后携带4-bp内含子插入的异常转录本，该插入导致移码并引入提前终止密码子；该转录本预计会被无义介导的mRNA降解所降解，或者如果被翻译，将产生无功能的截短蛋白，导致AK2功能丧失。根据ACMG/AMP标准，该变异被分类为致病性。由于无法获得患者来源材料，我们重新分析了来自AK2敲除的人造血干/祖细胞的公开RNA-seq数据（GSE179320），并鉴定出六个枢纽基因（APOE、TREM2、CD68、CD36、IRF8和CD163），我们进一步在AK2敲低的HL-60细胞中于mRNA水平验证了这些基因，其中IRF8显示出最显著的上调。结论：本研究表征了该变异引起的剪接缺陷，并鉴定了候选AK2相关基因；RD与B-ALL的共存被报道为一种需要进一步研究的临床观察。
英文摘要
Reticular dysgenesis (RD) is a rare autosomal recessive severe combined immunodeficiency characterized by profound neutropenia, T-cell lymphopenia and sensorineural hearing loss, and is caused by biallelic loss-of-function variants in AK2. We identified a homozygous AK2 splice-site variant (c.498 + 1G > A) in a boy with RD and concurrent B-cell acute lymphoblastic leukemia (B-ALL), a clinical combination not previously reported in association with an AK2 variant. An in vitro minigene assay showed that c.498 + 1G > A disrupts the canonical 5' splice donor site and generates an aberrant transcript carrying a 4-bp intronic insertion after exon 5, which causes a frameshift and introduces a premature termination codon; the transcript is predicted to be degraded by nonsense-mediated mRNA decay or, if translated, to yield a non-functional truncated protein, leading to loss of AK2 function. The variant was classified as pathogenic according to the ACMG/AMP criteria. As patient-derived material was unavailable, we re-analyzed publicly available RNA-seq data from AK2-knockout human hematopoietic stem and progenitor cells (GSE179320) and identified six hub genes (APOE, TREM2, CD68, CD36, IRF8 and CD163), which we further validated at the mRNA level in AK2-knockdown HL-60 cells, with IRF8 showing the most pronounced upregulation. This study characterizes the splicing defect caused by this variant and identifies candidate AK2-associated genes; the coexistence of RD and B-ALL is reported as a clinical observation requiring further investigation.