Nudix Hydrolases

  • 文章类型: Journal Article
    背景:硫唑嘌呤(AZA)是一种广泛使用的免疫抑制药物。白细胞减少是药物的严重不良反应,通常需要减少剂量或停药。白细胞减少症的预测因素包括遗传和非遗传因素。AZA代谢酶的遗传多态性,硫嘌呤S-甲基转移酶(TPMT)已建立。关于Nudix水解酶(NUDT15)基因多态性的作用尚无定论。这项病例对照研究评估了NUDT15和TPMT的遗传多态性与AZA诱导的白细胞减少症的关联。
    方法:病例为在开始治疗1年内出现白细胞减少症(白细胞计数<4000/μl)的AZA患者,需要减少剂量或停药。在用AZA治疗的1年内没有白细胞减少的年龄和性别匹配的患者作为对照。TPMT(3个位点:c238G至C,c460G到A,c719A到G)和NUDT15(c415C到T,rs116855232)基因分型使用TPMT试纸条测定和聚合酶链反应-限制性片段长度多态性进行,分别。注意到基因型频率,计算比值比以确定基因型与白细胞减少症之间的关联。
    结果:纳入29名受试者(15例和14例对照)。病例和对照之间的TPMT基因型(*1/*1和*1/*3C)未观察到统计学上的显着差异(P=0.23)。NUDT15基因型(*1/*1和*1/*3)(P=0.65)在病例和对照组之间也没有统计学上的显着差异。
    结论:在印度东部人群中,上述基因型似乎与AZA诱导的白细胞减少症无关。
    BACKGROUND: Azathioprine (AZA) is a widely used immunosuppressant drug. Leukopenia is a serious adverse effect of the drug which often necessitates dose reduction or drug withdrawal. Predictors of leukopenia include genetic and nongenetic factors. Genetic polymorphism of AZA-metabolizing enzyme, thiopurine S-methyltransferase (TPMT) is well established. There is inconclusive evidence about the role of Nudix hydrolase (NUDT15) gene polymorphism. This case-control study assessed the association of genetic polymorphisms of NUDT15 and TPMT with leukopenia induced by AZA.
    METHODS: Cases were patients on AZA who developed leukopenia (white blood cell count <4000/μl) within 1 year of treatment initiation that necessitated dose reduction or drug withdrawal. Age and gender-matched patients without leukopenia within 1 year of treatment with AZA served as controls. TPMT (3 loci: c238G to C, c460G to A, c719A to G) and NUDT15 (c 415C to T, rs116855232) genotyping were done using TPMT strip assay and polymerase chain reaction-restriction fragment length polymorphism, respectively. Genotype frequencies were noted, and the odds ratio was calculated to determine the association between genotypes and leukopenia.
    RESULTS: Twenty-nine subjects (15 cases and 14 controls) were enrolled. Statistically significant differences were not observed in the TPMT genotype (*1/*1 and *1/*3C) (P = 0.23) between cases and controls. NUDT15 genotypes (*1/*1 and *1/*3) (P = 0.65) also showed no statistically significant difference between cases and controls.
    CONCLUSIONS: The above genotypes do not appear to be associated with AZA-induced leukopenia in an eastern Indian population.
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  • 文章类型: Journal Article
    肌醇焦磷酸1,5-IP8调节裂变酵母磷酸盐稳态调节子的表达,通过其作为抑制PHOmRNA合成的上游lncRNAs转录早熟终止的激动剂的作用,包含磷酸获得基因pho1,pho84和tgp1。1,5-IP8水平由将5-IP7转化为1,5-IP8的Asp1N末端激酶结构域和三种肌醇焦磷酸酶-Asp1C末端结构域(组氨酸酸性磷酸酶)之间的平衡决定,Siw14(一种半胱氨酸磷酸酶),和Aps1(一种Nudix酶)。在这项研究中,我们报道了Aps1的生化和遗传特征,并分析了Asp1,Siw14和Aps1突变对细胞肌醇焦磷酸水平的影响.我们发现Aps1的底物库包括无机多磷酸盐,5-IP7、1-IP7和1,5-IP8。与5-IP7相比,Aps1对1-IP7的水解表现出〜两倍的偏好,与野生型细胞相比,aps1Δ细胞的1-IP7水平高两倍。虽然Aps1和Siw14都不是增长所必需的,在YES培养基上,aps1Δsiw14Δ双突变是致命的。这种致死性是IP8中毒的表现,由此,过量的1,5-IP8驱动tgp1的去抑制,导致Tgp1介导的甘油磷酸胆碱的摄取。我们能够在缺乏甘油磷酸胆碱的ePMGT培养基上恢复aps1Δsiw14突变体,并通过删除tgp1来抑制aps1Δsiw14在YES上的严重生长缺陷。然而,通过删除tgp1无法缓解aps1Δasp1-H397A菌株的严重生长缺陷,这表明该双焦磷酸酶突变体中的1,5-IP8水平超过了一个阈值,超过该阈值的过度热情终止会影响其他基因,导致细胞毒性。
    目的:通过lncRNA介导的干扰抑制裂殖酵母PHO基因tgp1,pho1和pho84对1,5-IP8代谢的变化敏感,1,5-IP8是一种信号分子,可作为早熟lncRNA终止的激动剂。1,5-IP8由5-IP7的磷酸化形成,并由来自三个不同酶家族的肌醇焦磷酸酶分解代谢:Asp1(组氨酸酸性磷酸酶),Siw14(一种半胱氨酸磷酸酶),和Aps1(一种Nudix水解酶)。这项研究需要对Aps1进行生化表征,并分析Asp1,Siw14和Aps1突变如何影响体内生长和肌醇焦磷酸池。Aps1催化无机多磷酸盐的水解,体外5-IP7、1-IP7和1,5-IP8,与5-IP7相比,1-IP7具有〜两倍的偏好。aps1细胞的1-IP7水平比野生型细胞高两倍。aps1Δsiw14Δ双突变是致命的,因为过量的1,5-IP8会触发tgp1的抑制,导致甘油磷酸胆碱的毒性摄取。
    Inositol pyrophosphate 1,5-IP8 regulates expression of a fission yeast phosphate homeostasis regulon, comprising phosphate acquisition genes pho1, pho84, and tgp1, via its action as an agonist of precocious termination of transcription of the upstream lncRNAs that repress PHO mRNA synthesis. 1,5-IP8 levels are dictated by a balance between the Asp1 N-terminal kinase domain that converts 5-IP7 to 1,5-IP8 and three inositol pyrophosphatases-the Asp1 C-terminal domain (a histidine acid phosphatase), Siw14 (a cysteinyl-phosphatase), and Aps1 (a Nudix enzyme). In this study, we report the biochemical and genetic characterization of Aps1 and an analysis of the effects of Asp1, Siw14, and Aps1 mutations on cellular inositol pyrophosphate levels. We find that Aps1\'s substrate repertoire embraces inorganic polyphosphates, 5-IP7, 1-IP7, and 1,5-IP8. Aps1 displays a ~twofold preference for hydrolysis of 1-IP7 versus 5-IP7 and aps1∆ cells have twofold higher levels of 1-IP7 vis-à-vis wild-type cells. While neither Aps1 nor Siw14 is essential for growth, an aps1∆ siw14∆ double mutation is lethal on YES medium. This lethality is a manifestation of IP8 toxicosis, whereby excessive 1,5-IP8 drives derepression of tgp1, leading to Tgp1-mediated uptake of glycerophosphocholine. We were able to recover an aps1∆ siw14∆ mutant on ePMGT medium lacking glycerophosphocholine and to suppress the severe growth defect of aps1∆ siw14∆ on YES by deleting tgp1. However, the severe growth defect of an aps1∆ asp1-H397A strain could not be alleviated by deleting tgp1, suggesting that 1,5-IP8 levels in this double-pyrophosphatase mutant exceed a threshold beyond which overzealous termination affects other genes, which results in cytotoxicity.
    OBJECTIVE: Repression of the fission yeast PHO genes tgp1, pho1, and pho84 by lncRNA-mediated interference is sensitive to changes in the metabolism of 1,5-IP8, a signaling molecule that acts as an agonist of precocious lncRNA termination. 1,5-IP8 is formed by phosphorylation of 5-IP7 and catabolized by inositol pyrophosphatases from three distinct enzyme families: Asp1 (a histidine acid phosphatase), Siw14 (a cysteinyl phosphatase), and Aps1 (a Nudix hydrolase). This study entails a biochemical characterization of Aps1 and an analysis of how Asp1, Siw14, and Aps1 mutations impact growth and inositol pyrophosphate pools in vivo. Aps1 catalyzes hydrolysis of inorganic polyphosphates, 5-IP7, 1-IP7, and 1,5-IP8 in vitro, with a ~twofold preference for 1-IP7 over 5-IP7. aps1∆ cells have twofold higher levels of 1-IP7 than wild-type cells. An aps1∆ siw14∆ double mutation is lethal because excessive 1,5-IP8 triggers derepression of tgp1, leading to toxic uptake of glycerophosphocholine.
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  • 文章类型: Journal Article
    目的:血液毒性是一种危及生命的疾病,已成为急性淋巴细胞白血病(ALL)患者停药的主要原因。据报道,nudix水解酶15(NUDT15)基因多态性(c.415C>T)与ALL患者维持治疗的6-巯基嘌呤(6-MP)的血液毒性有关。然而,印度尼西亚人群中这种遗传多态性的患病率尚不清楚。本研究旨在评估印度尼西亚小儿ALL患者NUDT15多态性的频率及其与6-MP血液毒性的相关性。
    方法:将来自接受6-MP治疗的ALL患儿的101份储存的DNA样本用于基因检测。进行直接测序以确定NUDT15c.415C>T基因型。采用卡方检验或Fisher精确检验检验NUDT15c.415C>T基因型与血液毒性之间的关联。
    结果:用6-MP治疗的ALL患者的所有DNA样本(100%)均表现出NUDT15c.415C>T基因型的纯合变体,其中70.3%有一定程度的血液毒性。我们发现NUDT15基因多态性在不同血液毒性状态的ALL患者中没有显着差异。
    结论:在我们的研究人群中观察到的NUDT15c.415C>T的高频率可能解释了印度尼西亚人群中儿童ALL患者中6-MP相关血液毒性的患病率升高。我们的研究为NUDT15基因多态性及其与血液毒性的关系提供了新的见解。需要进一步的研究来确定调整印度尼西亚小儿ALL患者6-MP初始剂量的必要性。
    OBJECTIVE: Hematotoxicity is a life-threatening condition that has become the major cause of drug discontinuation in patients with acute lymphoblastic leukemia (ALL). The nudix hydrolase 15 (NUDT15) gene polymorphism (c.415C>T) is reported to have an association with the hematotoxicity of 6-mercaptopurine (6-MP) as maintenance therapy in patients with ALL. However, the prevalence of this genetic polymorphism in the Indonesian population is unknown. This study aimed to assess the frequency of NUDT15 polymorphism among Indonesian pediatric patients with ALL and its association with the hematotoxicity of 6-MP.
    METHODS: A total of 101 stored DNA samples from pediatric patients with ALL receiving 6-MP treatment were used for genetic testing. Direct sequencing was conducted to determine the NUDT15 c.415C>T genotype. Chi-square or Fisher\'s exact test were employed to examine the association between the NUDT15 c.415C>T genotype and hematotoxicity.
    RESULTS: All (100%) of the DNA samples from patients with ALL treated with 6-MP exhibited a homozygous variant of the NUDT15 c.415C>T genotype, 70.3% of which showed hematotoxicity to some extent. We found no significant differences in NUDT15 gene polymorphism among patients with ALL with different states of hematotoxicity.
    CONCLUSIONS: The observed high frequency of NUDT15 c.415C>T in our study population might explain the elevated prevalence of 6-MP-associated hematotoxicity in pediatric patients with ALL within the Indonesian population. Our study provides new insight regarding the NUDT15 gene polymorphism and its relation to hematotoxicity. Further studies are required to determine the necessity of adjusting the initial dose of 6-MP for Indonesian pediatric patients with ALL.
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  • 文章类型: Journal Article
    背景:抗癌药物治疗仍然是治疗癌症的基石。由于影响药物反应和代谢的遗传因素,抗癌药物的有效性和安全性在个体之间存在显着差异。与抗癌治疗相关的斯里兰卡人的药物基因组变异数据很少。由于斯里兰卡目前的治疗指南通常不考虑当地的药物基因组变异,本研究旨在探索斯里兰卡人群中药物基因组变异的多样性,为个性化治疗方法铺平道路,并改善患者预后.
    方法:关于基因CYP2D6,DPYD,具有标记为证据水平1A-2B的临床注释的NUDT15、EPAS1和XRCC1从药物基因组学知识库数据库获得。他们在斯里兰卡的频率是从一个匿名数据库中获得的,该数据库来自541名在人类遗传学部门接受外显子组测序的斯里兰卡人,医学院,科伦坡大学。DPYD的变化,NUDT15和EPAS1基因与氟嘧啶的毒性增加有关,巯基嘌呤,和索拉非尼分别。CYP2D6和XRCC1基因的变异与他莫昔芬和铂化合物的功效变化有关,分别。计算这些变体的次要等位基因频率并与其他群体进行比较。
    结果:rs1065852c.100C>T(CYP2D6)的MAFs,rs3918290c.1905+1G>A(DPYD),rs56038477c.1236G>A(DPYD),rs7557402c.1035-7C>G(EPAS1),rs116855232c.415C>T(NUDT15*3),rs25487c.1196A>G(XRCC1)为:12.9%[95CI:10.9-14.9],1.5%[95CI:0.8-2.2],1.2%[95CI:0.5-1.8],37.7%[95CI:34.8-40.6],8.3%[95CI:6.7-10.0],和64.0%[95CI:61.1-66.8],分别。rs1065852c.100C>T(CYP2D6)的频率,rs7557402c.1035-7C>G(EPAS1),rs25487(XRCC1)在斯里兰卡明显较低,与某些西方和亚洲人群相比,斯里兰卡人的rs116855232c.415C>T(NUDT15*3)和rs56038477c.1236G>A(DPYD)的频率明显更高。
    结论:与索拉非尼(rs7557402c.84,131C>G)和,氟嘧啶(rs56038477c.1236G>A)和巯基嘌呤(rs116855232c.415C>T)的毒性风险更高,三苯氧胺(rs1065852c.100C>T)和铂化合物(rs25487)的有效性降低。这些发现强调了这些遗传变异对斯里兰卡人抗癌剂量需求的个体差异的潜在贡献。
    BACKGROUND: Therapy with anti-cancer drugs remain the cornerstone of treating cancer. The effectiveness and safety of anti-cancer drugs vary significantly among individuals due to genetic factors influencing the drug response and metabolism. Data on the pharmacogenomic variations in Sri Lankans related to anti-cancer therapy is sparse. As current treatment guidelines in Sri Lanka often do not consider local pharmacogenomic variants, this study aimed to explore the diversity of pharmacogenomic variants in the Sri Lankan population to pave the way for personalized treatment approaches and improve patient outcomes.
    METHODS: Pharmacogenomic data regarding variant-drug pairs of genes CYP2D6, DPYD, NUDT15, EPAS1, and XRCC1 with clinical annotations labelled as evidence levels 1A-2B were obtained from the Pharmacogenomics Knowledgebase database. Their frequencies in Sri Lankans were obtained from an anonymized database that was derived from 541 Sri Lankans who underwent exome sequencing at the Human Genetics Unit, Faculty of Medicine, University of Colombo. Variations in DPYD, NUDT15, and EPAS1 genes are related to increased toxicity to fluoropyrimidines, mercaptopurines, and sorafenib respectively. Variations in CYP2D6 and XRCC1 genes are related to changes in efficacy of tamoxifen and platinum compounds, respectively. Minor allele frequencies of these variants were calculated and compared with other populations.
    RESULTS: MAFs of rs1065852 c.100 C > T (CYP2D6), rs3918290 c.1905 + 1G > A (DPYD), rs56038477 c.1236G > A (DPYD), rs7557402 c.1035-7 C > G (EPAS1), rs116855232 c.415 C > T (NUDT15*3), and rs25487 c.1196 A > G (XRCC1) were: 12.9% [95%CI:10.9-14.9], 1.5% [95%CI:0.8-2.2], 1.2% [95%CI:0.5-1.8], 37.7% [95%CI:34.8-40.6], 8.3% [95%CI:6.7-10.0], and 64.0% [95%CI:61.1-66.8], respectively. Frequencies of rs1065852 c.100 C > T (CYP2D6), rs7557402 c.1035-7 C > G (EPAS1), and rs25487 (XRCC1) were significantly lower in Sri Lankans, while frequencies of rs116855232 c.415 C > T (NUDT15*3) and rs56038477 c.1236G > A (DPYD) were significantly higher in Sri Lankans when compared to some Western and Asian populations.
    CONCLUSIONS: Sri Lankans are likely to show lower toxicity risk with sorafenib (rs7557402 c.84,131 C > G) and, higher toxicity risk with fluoropyrimidines (rs56038477 c.1236G > A) and mercaptopurine (rs116855232 c.415 C > T), and reduced effectiveness with tamoxifen (rs1065852 c.100 C > T) and platinum compounds (rs25487). These findings highlight the potential contribution of these genetic variations to the individual variability in anti-cancer dosage requirements among Sri Lankans.
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  • 文章类型: Journal Article
    背景:这项研究评估了NUDT15密码子139基因分型在优化日本炎症性肠病(IBD)的硫代嘌呤治疗中的有效性,使用真实世界的数据,并旨在建立基于基因型的治疗策略。
    方法:对4628例接受NUDT15密码子139基因分型的IBD患者进行回顾性分析。这项研究评估了基因分型测试的目的以及获得的结果后的后续处方。结果在基因分型组(有基因分型试验的硫嘌呤)和非基因分型组(无基因分型试验的硫嘌呤)之间进行比较。通过基因型和先前的基因分型状态分析不良事件(AE)的危险因素。
    结果:用于医学目的的基因分型试验显示,Arg/Arg和Arg/Cys基因型之间的硫嘌呤诱导率没有显着差异,但有9名Arg/Cys患者选择退出噻嘌呤治疗。在基因分型组中,Arg/Arg患者接受的初始剂量高于非基因分型组,而Arg/Cys患者接受的Arg/Cys较低(中位数25mg/天)。基因分型组中发生的AE较少,因为它们在Arg/Cys病例中的发生率较低。从<25mg/天的AZA开始减少Arg/Cys患者的AE,而Arg/Arg患者在维持≥75mgAZA时保留率更好。恶心和肝损伤与硫代嘌呤制剂相关,但与剂量无关。pH依赖性美沙拉嗪降低了美沙拉嗪使用者白细胞减少的风险。
    结论:NUDT15密码子139基因分型可有效减少基于基因型的剂量调整后,IBD患者的噻嘌呤诱导的AE并改善治疗保留率。这项研究提供了基于基因型的数据驱动的治疗策略,并确定了特定AE的风险因素。有助于精制硫嘌呤治疗方法。
    This study evaluated the effectiveness of NUDT15 codon 139 genotyping in optimizing thiopurine treatment for inflammatory bowel disease (IBD) in Japan, using real-world data, and aimed to establish genotype-based treatment strategies.
    A retrospective analysis of 4628 IBD patients who underwent NUDT15 codon 139 genotyping was conducted. This study assessed the purpose of the genotyping test and subsequent prescriptions following the obtained results. Outcomes were compared between the Genotyping group (thiopurine with genotyping test) and Non-genotyping group (thiopurine without genotyping test). Risk factors for adverse events (AEs) were analyzed by genotype and prior genotyping status.
    Genotyping test for medical purposes showed no significant difference in thiopurine induction rates between Arg/Arg and Arg/Cys genotypes, but nine Arg/Cys patients opted out of thiopurine treatment. In the Genotyping group, Arg/Arg patients received higher initial doses than the Non-genotyping group, while Arg/Cys patients received lower ones (median 25 mg/day). Fewer AEs occurred in the Genotyping group because of their lower incidence in Arg/Cys cases. Starting with < 25 mg/day of AZA reduced AEs in Arg/Cys patients, while Arg/Arg patients had better retention rates when maintaining ≥ 75 mg AZA. Nausea and liver injury correlated with thiopurine formulation but not dosage. pH-dependent mesalamine reduced leukopenia risk in mesalamine users.
    NUDT15 codon 139 genotyping effectively reduces thiopurine-induced AEs and improves treatment retention rates in IBD patients after genotype-based dose adjustments. This study provides data-driven treatment strategies based on genotype and identifies risk factors for specific AEs, contributing to a refined thiopurine treatment approach.
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  • 文章类型: Journal Article
    肿瘤细胞必须重新连接核苷酸合成以满足不受约束的增殖的需求。同时,它们表现出增加的活性氧(ROS)产生,这矛盾地破坏DNA和游离的脱氧核糖核苷三磷酸(dNTP)。这些代谢过程如何整合到燃料肿瘤发生中仍有待研究。MYC家族癌蛋白协调核苷酸合成和ROS生成以驱动多种癌症的发展。我们在此进行了基于聚类的定期间隔短回文重复(CRISPR)的靶向代谢基因的功能筛选,并将nudix水解酶1(NUDT1)鉴定为MYC驱动的依赖性。机械上,MYC协调两个平行作用的代谢途径的平衡,NADPH氧化酶4(NOX4)-ROS途径和Polo样激酶1(PLK1)-NUDT1核苷酸消毒途径。我们将LC-1-40描述为一种有效的,在体内消耗NUDT1的目标降解剂。LC-1-40的给药引起过度的核苷酸氧化,患者源性异种移植物的细胞毒性和治疗反应。因此,NUDT1的药理学靶向代表了一种可行的MYC驱动的代谢倾向。
    Tumor cells must rewire nucleotide synthesis to satisfy the demands of unbridled proliferation. Meanwhile, they exhibit augmented reactive oxygen species (ROS) production which paradoxically damages DNA and free deoxy-ribonucleoside triphosphates (dNTPs). How these metabolic processes are integrated to fuel tumorigenesis remains to be investigated. MYC family oncoproteins coordinate nucleotide synthesis and ROS generation to drive the development of numerous cancers. We herein perform a Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-based functional screen targeting metabolic genes and identified nudix hydrolase 1 (NUDT1) as a MYC-driven dependency. Mechanistically, MYC orchestrates the balance of two metabolic pathways that act in parallel, the NADPH oxidase 4 (NOX4)-ROS pathway and the Polo like kinase 1 (PLK1)-NUDT1 nucleotide-sanitizing pathway. We describe LC-1-40 as a potent, on-target degrader that depletes NUDT1 in vivo. Administration of LC-1-40 elicits excessive nucleotide oxidation, cytotoxicity and therapeutic responses in patient-derived xenografts. Thus, pharmacological targeting of NUDT1 represents an actionable MYC-driven metabolic liability.
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  • 文章类型: Case Reports
    NUDT2是维持四磷酸二腺苷(Ap4A)细胞内水平的重要酶。NUDT2中功能变体的双等位基因缺失最近被报道为智力障碍(ID)的罕见原因。在这里,我们描述一个有身份证的中国女孩,注意缺陷多动障碍(ADHD),以及行走姿势异常和爬楼梯困难的运动延迟,具有复合杂合变体c.34C>T(p。R12*)和c.194T>G(p。I65R)在NUDT2中。纯合变体c.34C>T(p。R12*)或c.186del(p。NUDT2中的A63Qfs*3)以前曾被报告为原因ID。这是第一位由于NUDT2中的复合杂合变体而患有ID的患者,并且p.I65R是新的错义变体。这项研究丰富了NUDT2相关ID的基因型和表型,并支持NUDT2的关键发育参与。
    NUDT2 is an enzyme important for maintaining the intracellular level of the diadenosine tetraphosphate (Ap4A). Bi-allelic loss of function variants in NUDT2 has recently been reported as a rare cause of intellectual disability (ID). Herein, we describe a Chinese girl with ID, attention deficit hyperactivity disorder (ADHD), and motor delays with abnormal walking posture and difficulty climbing stairs, who bears compound heterozygous variants c.34 C > T (p.R12*) and c.194T > G (p.I65R) in NUDT2. Homozygous variants c.34 C > T (p.R12*) or c.186del (p.A63Qfs*3) in NUDT2 were previously reported to cause ID. This is the first patient with ID due to compound heterozygous variants in NUDT2 and p.I65R is a novel missense variant. This study enriched the genotype and phenotype of NUDT2-related ID and supported the critical developmental involvement of NUDT2.
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  • 文章类型: Journal Article
    背景:硫嘌呤如巯基嘌呤(MP)被广泛用于治疗急性淋巴细胞白血病(ALL)。硫嘌呤-S-甲基转移酶(TPMT)和Nudix水解酶15(NUDT15)灭活硫嘌呤,无功能变异与药物诱导的骨髓抑制有关。强烈建议在TPMT和NUDT15活性中度或完全丧失的患者中调整MP的剂量。然而,对于两种酶均具有中等活性的患者,推荐的剂量减少程度目前尚不清楚.
    方法:从新加坡的1768例ALL患者收集维持期间的MP剂量,危地马拉,印度,和北美。对患者进行TPMT和NUDT15的基因分型,并使用临床药物遗传学实施联盟(CPIC)定义的可操作变体将患者分类为TPMT和NUDT15正常代谢者(TPMT/NUDT15NM)。TPMT或NUDT15中间代谢剂(TPMTIM或NUDT15IM),或TPMT和NUDT15复合中间代谢剂(TPMT/NUDT15IM/IM)。并行,我们评估了MP毒性,新陈代谢,和使用Tpmt/Nudt15组合的杂合小鼠模型(Tpmt+/-/Nudt15+/-)的剂量调整。
    结果:队列中有22例患者(1.2%)为TPMT/NUDT15IM/IM,大多数人自我报告为西班牙裔(68.2%,15/22).TPMT/NUDT15IM/IM患者的每日MP剂量中位数为25.7mg/m2(四分位距[IQR],19.0-31.1mg/m2),显著低于TPMTIM和NUDT15IM剂量(P<.001)。同样,Tpmt+/-/Nudt15+/-小鼠表现出过度的造血毒性和积累更多的代谢产物(DNA-TG)比野生型或单杂合小鼠,基因型指导的MP剂量滴定有效缓解了这种情况。
    结论:我们建议在TPMT/NUDT15IM/IM患者中更大幅度地减少剂量以个体化MP治疗和减轻毒性。
    BACKGROUND: Thiopurines such as mercaptopurine (MP) are widely used to treat acute lymphoblastic leukemia (ALL). Thiopurine-S-methyltransferase (TPMT) and Nudix hydrolase 15 (NUDT15) inactivate thiopurines, and no-function variants are associated with drug-induced myelosuppression. Dose adjustment of MP is strongly recommended in patients with intermediate or complete loss of activity of TPMT and NUDT15. However, the extent of dosage reduction recommended for patients with intermediate activity in both enzymes is currently not clear.
    METHODS: MP dosages during maintenance were collected from 1768 patients with ALL in Singapore, Guatemala, India, and North America. Patients were genotyped for TPMT and NUDT15, and actionable variants defined by the Clinical Pharmacogenetics Implementation Consortium were used to classify patients as TPMT and NUDT15 normal metabolizers (TPMT/NUDT15 NM), TPMT or NUDT15 intermediate metabolizers (TPMT IM or NUDT15 IM), or TPMT and NUDT15 compound intermediate metabolizers (TPMT/NUDT15 IM/IM). In parallel, we evaluated MP toxicity, metabolism, and dose adjustment using a Tpmt/Nudt15 combined heterozygous mouse model (Tpmt+/-/Nudt15+/-).
    RESULTS: Twenty-two patients (1.2%) were TPMT/NUDT15 IM/IM in the cohort, with the majority self-reported as Hispanics (68.2%, 15/22). TPMT/NUDT15 IM/IM patients tolerated a median daily MP dose of 25.7 mg/m2 (interquartile range = 19.0-31.1 mg/m2), significantly lower than TPMT IM and NUDT15 IM dosage (P < .001). Similarly, Tpmt+/-/Nudt15+/- mice displayed excessive hematopoietic toxicity and accumulated more metabolite (DNA-TG) than wild-type or single heterozygous mice, which was effectively mitigated by a genotype-guided dose titration of MP.
    CONCLUSIONS: We recommend more substantial dose reductions to individualize MP therapy and mitigate toxicity in TPMT/NUDT15 IM/IM patients.
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  • 文章类型: Journal Article
    由RNA加工酶的遗传缺陷引起的RNA加工功能失调对神经系统产生深远的影响,导致神经发育状况。我们对来自10个独立家庭的18名儿童和年轻人的隐性神经系统疾病进行了表征,以智力障碍为代表,运动发育迟缓,和步态紊乱。在一些患者周围神经病中,call体异常,存在进行性基底神经节沉积物。该疾病与NUDT2中的罕见变异有关,NUDT2是一种mRNA脱盖和Ap4A水解酶,包括新颖的错义和帧内删除变体。我们表明,这些NUDT2变体导致酶活性的显著损失,强烈暗示NUDT2功能丧失是疾病的原因。NUDT2缺陷患者成纤维细胞表现出明显改变的转录组,伴随着mRNA半衰期和稳定性的变化。在NUDT2缺陷细胞中最上调的mRNA中,我们鉴定了宿主应答和干扰素应答基因.重要的是,使用Ap4A水解酶的mRNA去盖缺陷的回加实验强调了NUDT2去盖的丧失,因为该活性与mRNA稳态的改变有关。我们的结果证实NUDT2水解酶活性的降低或丧失与神经系统疾病有关。强调生理平衡的mRNA加工机制对神经元发育和稳态的重要性。
    Dysfunctional RNA processing caused by genetic defects in RNA processing enzymes has a profound impact on the nervous system, resulting in neurodevelopmental conditions. We characterized a recessive neurological disorder in 18 children and young adults from 10 independent families typified by intellectual disability, motor developmental delay and gait disturbance. In some patients peripheral neuropathy, corpus callosum abnormalities and progressive basal ganglia deposits were present. The disorder is associated with rare variants in NUDT2, a mRNA decapping and Ap4A hydrolysing enzyme, including novel missense and in-frame deletion variants. We show that these NUDT2 variants lead to a marked loss of enzymatic activity, strongly implicating loss of NUDT2 function as the cause of the disorder. NUDT2-deficient patient fibroblasts exhibit a markedly altered transcriptome, accompanied by changes in mRNA half-life and stability. Amongst the most up-regulated mRNAs in NUDT2-deficient cells, we identified host response and interferon-responsive genes. Importantly, add-back experiments using an Ap4A hydrolase defective in mRNA decapping highlighted loss of NUDT2 decapping as the activity implicated in altered mRNA homeostasis. Our results confirm that reduction or loss of NUDT2 hydrolase activity is associated with a neurological disease, highlighting the importance of a physiologically balanced mRNA processing machinery for neuronal development and homeostasis.
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  • 文章类型: Journal Article
    理由:骨关节炎(OA)的标志之一,最常见的退行性关节病,是衰老软骨细胞数量的增加。靶向衰老软骨细胞或导致衰老的信号机制可能是OA治疗的有希望的新治疗方法。然而,对软骨细胞衰老与OA之间的关键靶点和联系的理解尚不清楚.方法:从Nudt7-/-,Acot12-/-,缺乏Acot12和Nudt7(dKO)的双敲除小鼠,并应用于微阵列。在老年人中检测到叉头转录因子M1(FOXM1)的存在,dKO,内侧半月板(DMM)软骨和关节软骨细胞的不稳定,FoxM1过表达和乙酰辅酶A治疗对软骨稳态的影响使用免疫组织化学检查,实时定量PCR(qRT-PCR),细胞凋亡和增殖试验,和番红O染色。将Rho@PAA-MnO2(MnO2纳米片)或肝素-ACBP/COS-GA-siFoxM1(ACBP-siFoxM1)纳米颗粒递送到DMM软骨中。结果:这里,我们建议通过递送(FoxM1siRNA(siFoxM1)来特异性捕获乙酰辅酶A,以通过抑制软骨细胞衰老轴来防止软骨降解。dKO通过上调FoxM1刺激软骨细胞衰老,并导致严重的软骨破坏。我们发现,在OA发病过程中,dKO小鼠中乙酰辅酶A的积累可能是FoxM1上调的原因。此外,使用可注射的生物活性纳米颗粒(siFoxM1-ACBP-NP),通过植入MnO2纳米片或递送用乙酰辅酶A结合蛋白(ACBP)官能化的siFoxM1以捕获乙酰辅酶A来清除软骨细胞衰老诱导的活性氧(ROS)显着地抑制了DMM诱导的软骨破坏。结论:我们发现Acot12和Nudt7的缺失通过FoxM1的上调和乙酰辅酶A的积累刺激软骨细胞衰老,siFoxM1-ACBP-NP的应用是治疗OA的潜在治疗策略。
    Rationale: One of the hallmarks of osteoarthritis (OA), the most common degenerative joint disease, is increased numbers of senescent chondrocytes. Targeting senescent chondrocytes or signaling mechanisms leading to senescence could be a promising new therapeutic approach for OA treatment. However, understanding the key targets and links between chondrocyte senescence and OA remains unclear. Methods: Senescent chondrocytes were identified from Nudt7-/-, Acot12-/-, double-knockout mice lacking Acot12 and Nudt7 (dKO) and applied to microarray. The presence of forkhead transcription factor M1 (FOXM1) was detected in aged, dKO, and destabilization of the medial meniscus (DMM) cartilages and articular chondrocytes, and the effect of FoxM1 overexpression and acetyl-CoA treatment on cartilage homeostasis was examined using immunohistochemistry, quantitative real-time PCR (qRT-PCR), cell apoptosis and proliferation assay, and safranin O staining. Delivery of Rho@PAA-MnO2 (MnO2 nanosheet) or heparin-ACBP/COS-GA-siFoxM1 (ACBP-siFoxM1) nanoparticles into DMM cartilage was performed. Results: Here, we propose the specific capture of acetyl-CoA with the delivery of (FoxM1 siRNA (siFoxM1) to prevent cartilage degradation by inhibiting the axis of chondrocyte senescence. dKO stimulate chondrocyte senescence via the upregulation of FoxM1 and contribute to severe cartilage breakdown. We found that the accumulation of acetyl-CoA in the dKO mice may be responsible for the upregulation of FoxM1 during OA pathogenesis. Moreover, scavenging reactive oxygen species (ROS) induced by chondrocyte senescence via the implantation of MnO2 nanosheets or delivery of siFoxM1 functionalized with acetyl-CoA binding protein (ACBP) to capture acetyl-CoA using an injectable bioactive nanoparticle (siFoxM1-ACBP-NP) significantly suppressed DMM-induced cartilage destruction. Conclusion: We found that the loss of Acot12 and Nudt7 stimulates chondrocyte senescence via the upregulation of FoxM1 and accumulation of acetyl-CoA, and the application of siFoxM1-ACBP-NP is a potential therapeutic strategy for OA treatment.
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