Mak Chloe Miu, Lam Ching-Wan, Tam Sidney, Lai Ching-Lung, Chan Lik-Yuen, Fan Sheung-Tat, Lau Yu-Lung, Lai Jak-Yiu, Yuen Patrick, Hui Joannie, Fu Chun-Cheung, Wong Ka-Sing, Mak Wing-Lai, Tze Kong, Tong Sui-Fan, Lau Abby, Leung Nancy, Hui Aric, Cheung Ka-Ming, Ko Chun-Hung, Chan Yiu-Ki, Ma Oliver, Chau Tai-Nin, Chiu Alexander, Chan Yan-Wo
Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China.
Division of Clinical Biochemistry, Queen Mary Hospital, Hong Kong, China.
J Hum Genet. 2008;53(1):55-63. doi: 10.1007/s10038-007-0218-2. Epub 2007 Nov 22.
Wilson disease (WD), an autosomal recessive disorder of copper transport, is the most common inherited liver disorder in Hong Kong Chinese. This was the first local study to elucidate the molecular basis and establish an effective DNA-based diagnostic protocol. The ATP7B genes of 65 patients were amplified by polymerase chain reaction (PCR) and sequenced. Haplotype analysis was performed using D13S301, D13S314, and D13S316. The p.L770L/p.R778L status in 660 subjects was determined to estimate WD prevalence. Allele age of p.R778L was determined by the smallest homozygosity region between D13S301 and D13S270. We identified 42 different mutations with 17 being novel. p.R778L (17.3%) was the most prevalent. Exons 2, 8, 12, 13, and 16 harbored 70% mutations. Thirty-two haplotypes were associated with WD chromosomes. The estimated prevalence rate was 1 in 5,400. Three out of 660 normal subjects had p.L770L/p.R778L. In the remaining 657 individuals, neither p.L770L nor p.R778L was found. We characterized a Hong Kong Chinese-specific ATP7B mutation spectrum with great genetic diversity. Exons 2, 8, 12, 13, and 16 should be screened first. The perfect linkage disequilibrium suggested that p.R778L and its private polymorphism p.L770L originated from a single ancestor. This East-Asian-specific mutation p.R778L/p.L770L is aged at least 5,500 years.
威尔逊病（WD）是一种常染色体隐性铜转运障碍疾病，是香港华人中最常见的遗传性肝脏疾病。这是首次阐明其分子基础并建立基于DNA的有效诊断方案的本地研究。采用聚合酶链反应（PCR）对65例患者的ATP7B基因进行扩增并测序。使用D13S301、D13S314和D13S316进行单倍型分析。确定660名受试者的p.L770L/p.R778L状态以估计WD患病率。通过D13S301和D13S270之间最小纯合区域确定p.R778L的等位基因年龄。我们鉴定出42种不同突变，其中17种为新突变。p.R778L（17.3%）最为常见。外显子2、8、12、13和16携带了70%的突变。32种单倍型与WD染色体相关。估计患病率为1/5400。660名正常受试者中有3人具有p.L770L/p.R778L。在其余657名个体中，未发现p.L770L和p.R778L。我们确定了具有高度遗传多样性的香港华人特异性ATP7B突变谱。应首先对外显子2、8、12、13和16进行筛查。完全连锁不平衡表明p.R778L及其特有多态性p.L770L起源于单一祖先。这种东亚特异性突变p.R778L/p.L770L至少有5500年历史。
