Ma Qiang, Hu Ronghua, Hui Wuhan, Zhao Hong, Zou Dongmei, Liu Yan, Sun Wanling
Department of Hematology, Xuanwu Hospital, Capital Medical University, Beijing, 100053, China.
Biochem Genet. 2025 Apr;63(2):1436-1447. doi: 10.1007/s10528-024-10752-2. Epub 2024 Apr 3.
JAK2-unmutated erythrocytosis or non-polycythemia vera erythrocytosis is a rare condition comprising both acquired and hereditary forms. Although acquired erythrocytosis has been well-studied, hereditary erythrocytosis remains poorly studied. Genetic alterations associated with hereditary erythrocytosis include mutations in erythropoietin receptor and erythropoietin (EPO), altered oxygen affinity mutations, and variants associated with the oxygen-sensing pathway. We established a molecular diagnostic approach based on these genes and retrospectively evaluated. Peripheral blood from 56 erythrocytosis patients, lacking JAK2 mutation, were screened for oxygen-sensing pathway abnormalities. Two novel mutations were identified in the EGLN1 gene: NM_022051.2:c.712G > C (p.Gly238Arg) and NM_022051.2:c.122A > C (p.Tyr41Ser) in two patients separately. Notably, both reported heterozygous mutations were absent in the population database. Predictions using multiple computer software indicated that these two missense mutations were harmful and induced a highly conserved amino acid change in EGLN1. Patients with the two mutations exhibited normal serum EPO levels and high hemoglobin and hematocrit levels. Additionally, three other variants of genes were identified in the oxygen-sensing pathway, including endothelial PAS domain protein 1 (EPAS1) rs184760160(2/56), and EGLN1 rs186996510(2/56), rs555121182(2/56). These variants were categorized as benign or likely benign. Our findings provide a framework for etiological research and highlight the importance of screening for genetic mutations associated with erythrocytosis in clinical practice.
JAK2 未突变的红细胞增多症或非真性红细胞增多症性红细胞增多症是一种罕见病症，包括获得性和遗传性两种形式。虽然获得性红细胞增多症已得到充分研究，但遗传性红细胞增多症的研究仍较少。与遗传性红细胞增多症相关的基因改变包括促红细胞生成素受体和促红细胞生成素（EPO）的突变、氧亲和力改变突变以及与氧感应途径相关的变异。我们基于这些基因建立了一种分子诊断方法并进行回顾性评估。对 56 例缺乏 JAK2 突变的红细胞增多症患者的外周血进行氧感应途径异常筛查。在两名患者中分别在 EGLN1 基因中鉴定出两个新突变：NM_022051.2:c.712G＞C（p.Gly238Arg）和 NM_022051.2:c.122A＞C（p.Tyr41Ser）。值得注意的是，群体数据库中均未报告这两个杂合突变。使用多种计算机软件进行的预测表明，这两个错义突变具有有害性，并在 EGLN1 中诱导了高度保守的氨基酸变化。携带这两个突变的患者血清 EPO 水平正常，但血红蛋白和血细胞比容水平较高。此外，在氧感应途径中还鉴定出另外三个基因变异，包括内皮 PAS 结构域蛋白 1（EPAS1）rs184760160（2/56），以及 EGLN1 rs186996510（2/56）、rs555121182（2/56）。这些变异被归类为良性或可能良性。我们的研究结果为病因学研究提供了一个框架，并强调了在临床实践中筛查与红细胞增多症相关基因突变的重要性。
