Gupta A, Aikath D, Neogi R, Datta S, Basu K, Maity B, Trivedi R, Ray J, Das S K, Gangopadhyay P K, Ray K
Human Genetics and Genomics Division, Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road, Jadavpur, Kolkata, 700 032, India.
Hum Genet. 2005 Oct;118(1):49-57. doi: 10.1007/s00439-005-0007-y. Epub 2005 Oct 28.
Wilson disease (WD) is an autosomal recessive disorder caused by defects in the copper-transporting P-type ATPase gene (ATP7B) resulting in the accumulation of copper in the liver and the brain. We identified prevalent mutations in the ATP7B of Indian WD patients and attempted to correlate those with the disease phenotype. Patients from 62 unrelated families and their first-degree relatives comprising 200 individuals were enrolled in this study. Three dinucleotide repeat markers flanking WD locus and a few intragenic SNPs were used to determine the genotypes and construct haplotypes of the patients. Seven recurring haplotypes accounting for 58% of the total mutant chromosomes were identified, and four underlying defects in the ATP7B representing 37% of WD chromosomes were detected. In addition, five other rare mutations were characterized. Thus a total of nine mutations including five novel changes were identified in the ATP7B of WD patients. Interestingly, homozygotes for different mutations that would be expected to produce similar defective proteins showed significant disparity in terms of organ involvement and severity of the disease. We also observed WD patients with neurological symptoms with little or no manifestation of hepatic pathogenesis. In one WD family, the proband and a sib had remarkably different phenotypes despite sharing the same pair of mutant chromosomes. These findings suggest a potential role for yet unidentified modifying loci for the observed phenotypic heterogeneity among the WD patients.
威尔逊病（WD）是一种常染色体隐性疾病，由铜转运P型ATP酶基因（ATP7B）缺陷引起，导致铜在肝脏和大脑中蓄积。我们鉴定了印度WD患者ATP7B中的常见突变，并试图将这些突变与疾病表型相关联。本研究纳入了来自62个无亲缘关系家庭的患者及其包括200人的一级亲属。使用位于WD基因座侧翼的三个二核苷酸重复标记和一些基因内单核苷酸多态性来确定患者的基因型并构建单倍型。鉴定出七种反复出现的单倍型，占总突变染色体的58%，并检测到ATP7B中的四个潜在缺陷，占WD染色体的37%。此外，还鉴定了其他五个罕见突变。因此，在WD患者的ATP7B中总共鉴定出九个突变，包括五个新变化。有趣的是，预期会产生相似缺陷蛋白的不同突变的纯合子在器官受累和疾病严重程度方面表现出显著差异。我们还观察到有神经症状的WD患者几乎没有或没有肝脏发病机制的表现。在一个WD家族中，先证者和一个同胞尽管共享同一对突变染色体，但具有明显不同的表型。这些发现表明，尚未确定的修饰基因座可能在WD患者观察到的表型异质性中发挥作用。
