High frequency of two mutations in codon 778 in exon 8 of the ATP7B gene in Taiwanese families with Wilson disease.

Abstract

The gene for Wilson disease (WD) has been cloned as a P type copper transporter gene (ATP7B). To elucidate the possible genetic mechanism for the diversity of clinical manifestations, we characterised 22 Taiwanese families with WD by microsatellite haplotyping of close DNA markers D13S314-D13S301-D13S316. We also screened for mutations of codon 778 in the transmembrane region. There were at least 15 haplotypes within eight broad subgroups observed among 44 WD chromosomes. Among the 22 unrelated patients, we found that six patients (27%) carried a codon 778 mutation. Nucleotide sequence analysis showed there were two different mutations: the previously reported Arg778Leu mutation in four patients and Arg778Gln, a new mutation, in two patients. The two different mutations of the same codon occurred in two distinct microsatellite haplotypes.

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.…”

“…The allele-size definitions of D13S314 and D13S316 were based on GDB:309065 and GDB:309089, respectively (http://www.gdb.org/gdb/). That of D13S301 was modified from previously published data (Chuang et al 1996;Thomas et al 1994), with additional allele sizes of 154 and 156 assigned as -1 and -2, respectively.…”

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

“…Because of the high heterogeneity of the Wilson disease mutation spectrum in Taiwanese, haplotype analysis was suggested to be the initial step before full-scale mutation analysis was performed in newly recruited WND patients. The haplotype data of WND chromosomes was compared with data in a previous study performed by Chuang et al (1996). In their study, only R778L and R778Q were identified, and were reported to be associated with haplotypes 8-4-4 and 8-1-6, respectively.…”

“…Some WND mutations, e.g., R778L, P992L, A874V, 2304insC, and N1270S, were identified in both Taiwanese and Japanese (Chuang et al 1996;Nanji et al 1997;Tsai et al 1998;Yamaguchi et al 1998). It would be interesting to determine whether these common mutations also shared the same haplotypes in these two ethnic populations.…”

“…With the majority of WND mutant alleles being identified in Taiwan, we investigated whether those alleles were associated with specific haplotypes. Haplotype analysis, using three short tandem repeat (STR) markers, D13S314, D13S301, and D13S316, has been shown to be a useful indicator of WND mutation (Thomas et al 1995;Nanji et al 1997;Chuang et al 1996). With the use of these three STR markers, haplotypes of all WND chromosomes were established.…”