Regional distribution of mutations of the ATP7B gene in patients with Wilson disease: impact on genetic testing

Abstract

Wilson disease is an autosomal recessive inherited disorder of copper metabolism. The Wilson disease gene codes for a copper transporting P-type ATPase (ATP7B). Molecular genetic analysis reveals at least 300 distinct mutations. While most reported mutations occur in single families, a few are more common. The most common mutation in patients from Central, Eastern, and Northern Europe is the point mutation H1069Q (exon 14). About 50-80% of Wilson disease (WD) patients from these countries carry at least one allele with this mutation with an allele frequency ranging between 30 and 70%. Other common mutations in Central and Eastern Europe are located on exon 8 (2299insC, G710S), exon 15 (3400delC) and exon 13 (R969Q). The allele frequency of these mutations is lower than 10%. In Mediterranean countries there is a wide range of mutations, the frequency of each of them varies considerably from country to country. In Sardinia, a unique deletion in the 5' UTR (-441/-427 del) is very frequent. In mainland Spain the missense mutation M645R in exon 6 is particularly common. Data from non-European countries are scarce. Most data from Asia are from Far Eastern areas (China, South Korea and Japan) where the R778L missense mutation in exon 8 is found with an allele frequency of 14-49%. In summary, given the constant improvement of analytic tools genetic testing will become an integral part for the diagnosis of WD. Knowledge of the differences in the worldwide distribution of particular mutations will help to design shortcuts for genetic diagnosis of WD.

Identification of a novel Wilson disease gene mutation frequent in Upper Austria: a genetic and clinical study

“…Only a few have been found with high frequency in WD patients such as the p.H1069Q(c.3207C4A) amino-acid substitution, the most common mutation in patients of Middle or East-European ancestry. 9,10 In other regions, other mutations are more frequent, like in Sardinia (c. À441_ À427del), in Spain (p.Met645Arg(c.1934T4G), exon 6) or in the Canary Islands (p.Leu708(Proc.2123T4C), exon 8). [11][12][13] Most of the other mutations appear at low frequency and are associated with specific ethnic groups, or occur within single families.…”

“…Other common mutations include p.Gly710Ser (c.2128G4A), exon 8), p.P767P-fs (2298-2299insC, exon 8) and p.Arg969Gln(c.2906G4A, exon 13). 9 In the present study, we present clinical features of 16 patients with WD originating from a distinct geographical area in the federal state of Upper Austria carrying a novel mutation in exon 9 (R816S(c.2448G4T)) of ATP7B.…”

Wilson's disease in Southern Brazil: genotype-phenotype correlation and description of two novel mutations in ATP7B gene

“…In most ethnic groups, either one or a small number of ATP7B mutations are prevalent, followed by many other rare mutations. Knowledge of the regional distribution of WD gene mutations is important when designing the appropriate screening strategies 9 .…”

Mutational Analysis of Exon 10 and Exon 13 of Atp7b Gene in Patients With Wilson’s Disease.

“…While most reported mutations occur in single families, only few mutations are more common. However, there is a wide range of mutations and the frequency of each of them varies considerably from country to country (Ferenci 2006). …”

“…Worldwide there is a dramatic improvement of analytic tools and the genetic testing became an integral part for the diagnosis of WD (Ferenci 2006). The identification of distribution of particular mutations will help to design shortcuts for genetic diagnosis of WD.…”