Yoo Han-Wook
Department of Pediatrics, Medical Genetics Clinic & Laboratory, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Genet Med. 2002 Nov-Dec;4(6 Suppl):43S-48S. doi: 10.1097/00125817-200211001-00009.
Wilson disease, an autosomal recessive disorder of copper transport, is probably the most common inherited metabolic disorder in Korea. In Wilson disease, synthesis of a defective copper transporting enzyme leads to the accumulation of copper in the liver, brain, and kidney. The product of the Wilson disease gene is a copper transporting P-type ATPase (ATP7B). In this study, efforts were made to identify novel mutations and investigate the frequency of the common mutations in Korean patients with Wilson disease.
This study includes 37 patients from 33 unrelated Korean families with Wilson disease. Genomic DNA from peripheral leukocytes or skin fibroblasts and cDNA from liver tissue were polymerase chain reaction-amplified exon by exon and subsequently analyzed using heteroduplex or single-strand conformation polymorphism analysis. Specimens showing mobility shift on those studies were directly sequenced.
Twelve different mutations in 33 Korean families with Wilson disease were identified: Arg778Leu (R778L), Asn1270Ser (N1270S), Ala874Val (A874V), 2303-2305delC, 2630-2656del, 2460-2462insC, Cys656Stop (C656X), Pro768His (P768H), Leu1083Phe (L1083F), Ala1168Ser (A1168S), Leu1255Ile (L1255I), and Asp1267Ala (D1267A). Among these, six mutations (2630-2656del, 2460-2462insC, C656X, P768H, A1168S, and L1255I) are novel. The R778L mutation is known to be highly prevalent in Asian patients. The allele frequency of R778L in Korean patients with Wilson disease was 37.9%, which was significantly higher than those of Japanese and Taiwanese patients. The N1270S mutation, originally described in an Italian patient, was the next most common mutation in Korean patients, with an allele frequency of 12.1%, which was presumed to disrupt the ATP hinge domain of the ATP7B protein. The A874V mutation was the third most common mutation with an allele frequency of 9.4%, which was presumed to disrupt the Td domain of the ATP7B protein.
The R778L, N1270S, and A874V mutations are three major mutations representing approximately 60% of mutated alleles, although Korean patients with Wilson disease are genetically heterogeneous.
威尔逊病是一种常染色体隐性铜转运障碍疾病，可能是韩国最常见的遗传性代谢疾病。在威尔逊病中，有缺陷的铜转运酶的合成导致铜在肝脏、大脑和肾脏中蓄积。威尔逊病基因的产物是一种铜转运P型ATP酶（ATP7B）。在本研究中，我们致力于鉴定新的突变，并调查韩国威尔逊病患者中常见突变的频率。
本研究纳入了来自33个无关韩国家庭的37例威尔逊病患者。来自外周血白细胞或皮肤成纤维细胞的基因组DNA以及来自肝脏组织的cDNA通过聚合酶链反应逐个外显子进行扩增，随后使用异源双链或单链构象多态性分析进行检测。在这些研究中显示迁移率改变的样本直接进行测序。
在33个韩国威尔逊病家庭中鉴定出12种不同的突变：Arg778Leu（R778L）、Asn1270Ser（N1270S）、Ala874Val（A874V）、2303 - 2305delC、2630 - 2656del、2460 - 2462insC、Cys656Stop（C656X）、Pro768His（P768H）、Leu1083Phe（L1083F）、Ala1168Ser（A1168S）、Leu1255Ile（L1255I）和Asp1267Ala（D1267A）。其中，6种突变（2630 - 2656del、2460 - 2462insC、C656X、P768H、A1168S和L1255I）是新发现的。已知R778L突变在亚洲患者中高度流行。韩国威尔逊病患者中R778L的等位基因频率为37.9%，显著高于日本和台湾患者。最初在一名意大利患者中描述的N1270S突变是韩国患者中第二常见的突变，等位基因频率为12.1%，推测该突变破坏了ATP7B蛋白的ATP铰链结构域。A874V突变是第三常见的突变，等位基因频率为9.4%，推测该突变破坏了ATP7B蛋白的Td结构域。
R778L、N1270S和A874V突变是三个主要突变，约占突变等位基因的60%，尽管韩国威尔逊病患者在基因上具有异质性。
