Molecular analysis of Wilson disease in Taiwan: identification of one novel mutation and evidence of haplotype-mutation association

Abstract

Wilson disease (WND) is caused by a deficiency of the copper-transporting enzyme, P-type ATPase (ATP7B). Twelve different mutations have previously been identified in Taiwan Chinese with Wilson disease. We, herein, report another 4 missense mutations, 1 of which is novel. We did haplotype analysis of Taiwanese WND chromosomes, using three well characterized short tandem repeat markers (haplotype was assigned in the order of D13S314-D13S301-D13S316). Association correlation was found between the mutations and their respective haplotypes. Haplotype-deduced pedigree analysis was shown to be helpful in the mutation analysis of WND chromosomes and in the molecular assessment of both pre-symptomatic WND patients and carriers. Given the complexity and heterogeneity of the mutation spectrum of ATP7B, we suggest that haplotype analysis should be performed before full-scale mutation analysis.

Mutational analysis of 65 Wilson disease patients in Hong Kong Chinese: Identification of 17 novel mutations and its genetic heterogeneity

“…Mutation p.R778L also has been observed on two other different microsatellite haplotypes (8-4-4 and 8-4-5.5) in Taiwanese (Chuang et al 1996;Lee et al 2000) and five microsatellite haplotypes (5-5-6, 5-7-4, 5-7-5, 5-7-5.5, and 5-7-7) in Japanese (Nanji et al 1997). Nonetheless, despite the various associated microsatellite haplotypes, p.R778L in the Han population is always linked to the polymorphism p.L770L, which does not coexist with other p.R778 missense mutations and has not been reported in other ethnic groups.…”

“…At the same amino acid 778 position, Caucasians have other amino acid substitutions. They were c.2332C [ G or p.R778G in Turkish (Figus et al 1995) and Greek patients (Loudianos et al 1998a), c.2333G [ A or p.R778Q in Greek (Loudianos et al 1998a), and c.2332C[T or p.R778W in North American (Shah et al 1997), Italian (Loudianos et al 1998b), Sardinian (Loudianos et al 1999) and British patients (Butler et al 2001;Curtis et al 1999), whereas these mutations have never been reported in Chinese patients, except p.R778Q (Lee et al 2000).…”

“…In our experience, WD is the most common inherited liver disease in Hong Kong Han Chinese. The mutation spectrum of the ATP7B gene is population specific even within East Asia (Ferenci 2006;Kenney and Cox 2007;Lee et al 2000;Park et al 2007;Shimizu et al 1999;Wan et al 2006). Therefore, data from other areas cannot be directly applicable for diagnostic purposes.…”

Clinical and molecular characterization of Wilson's disease in China: identification of 14 novel mutations

“…In studies of Caucasian populations, the p.His1069Gln mutation represents 37% to 63% of mutations [3,22]; however, the frequency and distribution of ATP7B mutations in Chinese WND patients has not been well studied. Only a few articles have reported ATP7B mutations in the Chinese population [23-31], and most of these studied only WND patients in the southern part of China. The present study therefore aimed to broaden the knowledge of ATP7B mutations in Chinese patients to determine whether genotype/phenotype correlations could be established.…”

Mutation Analysis and Characterization of Alternative Splice Variants of the Wilson Disease Gene ATP7B

“…Many therapeutic approaches have been explored to modify the splicing pattern of mutant pre‐messenger RNA (pre‐mRNA) or eliminate mRNA with a disease‐causing mutation. For example, skipping exons 6, 7, 8, 12, and 13 maintains the open reading frame of the ATP7B gene,9 and exons 8, 12, and 13 are mutation hotspots in Taiwanese patients 1, 2, 12, 13. Thus, it would useful to identify the function of alternatively spliced variants to determine whether splice‐correction therapy can be used for WD.…”