鉴定新型致病变体及其对二叶酸减少酶缺乏症临床表现的影响
Dandan Wang1, Dengyu Zhou1, Yuanyuan Zhang1
1Department of Pediatrics, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China.
Neuroscience
|August 2, 2025
概括
稀有代谢障碍的二叶酸减少酶 (DHFR) 缺乏会导致严重的贫血和神经问题. 基因检测对于早期诊断和改善受影响儿童的结果至关重要.
科学领域:
- 遗传学 遗传学 是一个
- 生物化学 生物化学
- 儿科 儿科 儿科
背景情况:
- 双叶酸减少酶 (DHFR) 缺乏症是一种罕见的自体逆向性疾病,影响叶酸代谢.
- 它对于DNA/RNA合成和正常生长至关重要,全球仅有7例确诊病例报告.
- 受影响的个体通常呈现出巨细胞性贫血和神经症状.
研究的目的:
- 在一个中国家庭中报告两例新的DHFR缺陷病例.
- 为了确定这些患者患有疾病的遗传变异.
- 阐明DHFR缺陷背后的分子机制.
主要方法:
- 进行全外体序列测序以确定遗传变异.
- 使用结构建模来预测变异对DHFR蛋白的影响.
- 为了评估蛋白质的稳定性,丰度和功能,进行了西斑,ELISA和甲状腺素结合试验.
主要成果:
- 在这两位患者中都发现了DHFR的两种复合异构变异 (p.Gly18Val和p.Pro26Leu).
- 结构建模表明,这些变异会损害DHFR蛋白的稳定性和功能.
- 变异性蛋白质的丰度减少,甲状腺素结合能力受损,证实了病原性.
结论:
- 鉴定的DHFR变异导致蛋白质水平降低和分子相互作用改变,导致DHFR缺乏.
- 早期基因检测对于患有不明原因的大质芽细胞贫血症或神经症状的患者至关重要.
- 及时诊断和治疗可以改善预后,并预防DHFR缺乏的严重后果.
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