Abstract

Wilson’s disease (WD) is an autosomal recessive condition caused by an impaired copper metabolism due to hereditary mutations in the ATP7B gene; the spectrum and frequency of mutations are considerably different in different populations. The goal of the study was to determine the most frequent mutations in the ATP7B gene in patients from Ukraine for the introduction of genetic testing into the practice of medical and genetic consulting. The materials for the study were DNA samples isolated from the leukocytes of 90 patients (41 males and 49 females), aged 3–60 with clinical and biochemical signs of the disease. The molecular and genetic analysis of the mutation c.3207C > A (H1069Q), the most common among Europeans, was conducted by the PCR Bi-PASA method. The sequencing of exons of the ATP7B gene was conducted for 23 patients who had a score of three or higher according to the Leipzig scoring system. The molecular and genetic analysis of the mutations in the ATP7B gene genetically verified Wilson’s disease in 23.3% of patients with clinical signs of the disease. Five different mutations and five single-nucleotide polymorphisms in the ATP7B gene were determined in the patients of the investigated group. The mutation c.3207C > A, most common for Europeans, was determined in 28 patients, including 15 cases of homozygosity. In six cases, the mutation c.3207C > A was in a compound heterozygosity state with other mutations in the ATP7B gene: 3–c.2304dupC (8 exon), 1–c.2128G > A (8 exon), 1–c.3011AC (13 exon), 1–c.3402delC (15 exon). No other transformations, except for mutation H1069Q, were found in seven people. The frequency of the pathogenic allele c.3207C > A (H1069Q) of the ATP7B gene, most widespread in Europe, among patients who had a score of three and higher according to the scoring system of diagnostic tests, was 76.8%. The frequency of allele c.2304dupC among genetically verified cases was 7%. The genetic testing of two mutations in the ATP7B gene (c.3207C > A and c.2304dupC), frequent among patients from Ukraine with Wilson’s disease, was introduced into practice. A third of patients did not have pathogenic alleles in exon sequences of the ATP7B gene but had one or several single nucleotide polymorphisms, including several nonpathogenic variants and one polymorphism associated with the increased risk of developing Alzheimer’s disease (c.2495A > G). The obtained results indicate the high informative value from genetic testing of c.3207C > A and c.2304dupC mutations in the ATP7B gene among Ukrainian patients with Wilson’s disease.

中文翻译：

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乌克兰威尔逊氏病高风险患者的ATP7B基因突变

摘要

威尔逊氏病（WD）是由于ATP7B基因的遗传突变导致铜代谢受损而引起的常染色体隐性遗传疾病。不同人群中突变的频谱和频率有很大不同。该研究的目的是确定ATP7B中最常见的突变将来自乌克兰的患者的基因用于医学和遗传咨询实践中的基因检测。该研究的材料是从90例3至60岁的患者的白细胞中分离出的DNA样本，这些患者具有该疾病的临床和生化迹象。通过PCR Bi-PASA方法对欧洲人中最常见的突变c.3207C> A（H1069Q）进行了分子和遗传分析。ATP7B基因外显子的测序是根据莱比锡（Leipzig）评分系统对得分在3分以上的23位患者进行的。ATP7B突变的分子和遗传分析该基因通过遗传学证实，在23.3％的患有威尔逊氏病的临床症状患者中。在研究组的患者中确定了ATP7B基因的五个不同突变和五个单核苷酸多态性。在欧洲人中最常见的突变c.3207C> A已在28例患者中确定，其中包括15例纯合性。在六种情况下，突变c.3207C> A与ATP7B基因的其他突变处于复合杂合状态：3–c.2304dupC（8外显子），1–c.2128G> A（8外显子），1–c .3011A C（13外显子），1–c.3402delC（15外显子）。除突变H1069Q外，在7个人中没有发现其他转化。ATP7B基因的致病性等位基因c.3207C> A（H1069Q）的频率，最普遍，在欧洲，患者谁了比分三和更高根据诊断测试的评分系统中，为76.8％。经过基因验证的病例中，c.2304dupC等位基因的发生率为7％。在乌克兰威尔逊氏病患者中频繁进行的ATP7B基因两个突变（c.3207C> A和c.2304dupC）的基因检测已被引入实践。三分之一的患者在ATP7B的外显子序列中没有致病的等位基因该基因具有一个或几个单核苷酸多态性，包括几种非致病性变异和一种与罹患阿尔茨海默氏病风险增加相关的多态性（c.2495A> G）。所得结果表明，通过基因检测乌克兰威尔逊氏病患者的ATP7B基因c.3207C> A和c.2304dupC突变，具有很高的参考价值。