Lesch-Nyhan综合征(LN)是一种X连锁隐性先天性代谢错误,是由于嘌呤救助酶次黄嘌呤-鸟嘌呤磷酸核糖基转移酶(HPRT)的缺乏而引起的。这种疾病表现得很严重,导致智力缺陷和其他神经异常,高凝状态,不受控制的自我伤害,还有痛风.别嘌呤醇用于缓解痛风,其他症状了解较少,阻碍治疗。在这里,我们对3例携带新型S162NHPRT1突变的儿童同胞的红细胞(RBC)进行了高通量的多组学分析.来自父母双方-母亲的红细胞,杂合携带者,和父亲,还分析了临床健康对照。LN红细胞的整体代谢分析显示丙酮酸激酶上游糖酵解中间体的积累,不饱和脂肪酸,和长链酰基肉碱.同样,高度不饱和磷脂酰胆碱在LN红细胞中也升高,而游离胆碱减少。细胞内铁,锌,硒,LN红细胞中的钾和钾也降低。全球蛋白质组学记录了红细胞膜蛋白的变化,血红蛋白,氧化还原稳态蛋白质,和凝血蛋白的富集。这些变化伴随着LN儿童和携带者母亲中蛋白质谷氨酰胺脱酰胺和甲基化的升高。在目前接受这种治疗的两个年长的兄弟姐妹中,用别嘌呤醇治疗不完全逆转了观察到的表型。这个独特的数据集为针对LN相关后遗症的潜在疗法的研究提供了新的机会。
Lesch-Nyhan syndrome (LN) is an is an X-linked recessive inborn error of metabolism that arises from a deficiency of purine salvage enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). The disease manifests severely, causing intellectual deficits and other neural abnormalities, hypercoagulability, uncontrolled self-injury, and gout. While allopurinol is used to alleviate gout, other symptoms are less understood, impeding treatment. Herein, we present a high-throughput multi-omics analysis of red blood cells (RBCs) from three pediatric siblings carrying a novel S162N HPRT1 mutation. RBCs from both parents-the mother, a heterozygous carrier, and the father, a clinically healthy control-were also analyzed. Global metabolite analysis of LN RBCs shows accumulation of glycolytic intermediates upstream of pyruvate kinase, unsaturated fatty acids, and long chain acylcarnitines. Similarly, highly unsaturated phosphatidylcholines are also elevated in LN RBCs, while free choline is decreased. Intracellular iron, zinc, selenium, and potassium are also decreased in LN RBCs. Global proteomics documented changes in RBC membrane proteins, hemoglobin, redox homeostasis proteins, and the enrichment of coagulation proteins. These changes were accompanied by elevation in protein glutamine deamidation and methylation in the LN children and carrier mother. Treatment with allopurinol incompletely reversed the observed phenotypes in the two older siblings currently on this treatment. This unique data set provides novel opportunities for investigations aimed at potential therapies for LN-associated sequelae.