Nemethova Martina, Radvanszky Jan, Kadasi Ludevit, Ascher David B, Pires Douglas E V, Blundell Tom L, Porfirio Berardino, Mannoni Alessandro, Santucci Annalisa, Milucci Lia, Sestini Silvia, Biolcati Gianfranco, Sorge Fiammetta, Aurizi Caterina, Aquaron Robert, Alsbou Mohammed, Lourenço Charles Marques, Ramadevi Kanakasabapathi, Ranganath Lakshminarayan R, Gallagher James A, van Kan Christa, Hall Anthony K, Olsson Birgitta, Sireau Nicolas, Ayoob Hana, Timmis Oliver G, Sang Kim-Hanh Le Quan, Genovese Federica, Imrich Richard, Rovensky Jozef, Srinivasaraghavan Rangan, Bharadwaj Shruthi K, Spiegel Ronen, Zatkova Andrea
Institute of Molecular Physiology and Genetics, Slovak Academy of Sciences, Bratislava, Slovakia.
Department of Molecular Biology, Faculty of Natural Sciences, Comenius university, Bratislava, Slovakia.
Eur J Hum Genet. 2016 Jan;24(1):66-72. doi: 10.1038/ejhg.2015.60. Epub 2015 Mar 25.
Alkaptonuria (AKU) is an autosomal recessive disorder caused by mutations in homogentisate-1,2-dioxygenase (HGD) gene leading to the deficiency of HGD enzyme activity. The DevelopAKUre project is underway to test nitisinone as a specific treatment to counteract this derangement of the phenylalanine-tyrosine catabolic pathway. We analysed DNA of 40 AKU patients enrolled for SONIA1, the first study in DevelopAKUre, and of 59 other AKU patients sent to our laboratory for molecular diagnostics. We identified 12 novel DNA variants: one was identified in patients from Brazil (c.557T>A), Slovakia (c.500C>T) and France (c.440T>C), three in patients from India (c.469+6T>C, c.650-85A>G, c.158G>A), and six in patients from Italy (c.742A>G, c.614G>A, c.1057A>C, c.752G>A, c.119A>C, c.926G>T). Thus, the total number of potential AKU-causing variants found in 380 patients reported in the HGD mutation database is now 129. Using mCSM and DUET, computational approaches based on the protein 3D structure, the novel missense variants are predicted to affect the activity of the enzyme by three mechanisms: decrease of stability of individual protomers, disruption of protomer-protomer interactions or modification of residues in the region of the active site. We also present an overview of AKU in Italy, where so far about 60 AKU cases are known and DNA analysis has been reported for 34 of them. In this rather small group, 26 different HGD variants affecting function were described, indicating rather high heterogeneity. Twelve of these variants seem to be specific for Italy.
黑尿症（AKU）是一种常染色体隐性疾病，由尿黑酸1,2 -双加氧酶（HGD）基因突变引起，导致HGD酶活性缺乏。DevelopAKUre项目正在进行，以测试nitisinone作为一种特异性治疗方法，来对抗苯丙氨酸 - 酪氨酸分解代谢途径的这种紊乱。我们分析了参与DevelopAKUre的第一项研究SONIA1的40例AKU患者以及送到我们实验室进行分子诊断的59例其他AKU患者的DNA。我们鉴定出12种新的DNA变体：一种在来自巴西（c.557T>A）、斯洛伐克（c.500C>T）和法国（c.440T>C）的患者中鉴定出，三种在来自印度的患者中（c.469+6T>C、c.650-85A>G、c.158G>A），六种在来自意大利的患者中（c.742A>G、c.614G>A、c.1057A>C、c.752G>A、c.119A>C、c.926G>T）。因此，HGD突变数据库中报告的380例患者中发现的潜在导致AKU的变体总数现在为129种。使用基于蛋白质3D结构的计算方法mCSM和DUET，预测这些新的错义变体通过三种机制影响酶的活性：单个原体稳定性降低、原体 - 原体相互作用破坏或活性位点区域残基修饰。我们还概述了意大利的AKU情况，到目前为止已知约60例AKU病例，其中34例已报告进行了DNA分析。在这个相当小的群体中，描述了26种影响功能的不同HGD变体，表明异质性相当高。其中12种变体似乎是意大利特有的。
