Ferenci, P. Regional distribution of mutations of the ATP7B gene in patients with Wilson disease: impact on genetic testing. Hum. Genet. 120, 151-159

Department of Internal Medicine IV, University of Vienna, Währinger Gürtel 18-20, 1090, Vienna, Austria.
Human Genetics (Impact Factor: 4.52). 10/2006; 120(2):151-9. DOI: 10.1007/s00439-006-0202-5
Source: PubMed

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.

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    • "For instance, Cu acts as an essential co-factor of a variety of enzymes such as cytochrome c oxidase and Cu,Zn superoxide dismutase [3] [4]. However, excess Cu can become toxic, as in the case of Wilson disease (WD), a human pathology characterized by Cu accumulation in the liver [5] resulting in acute liver failure or cirrhosis [6]. Reported mechanisms underlying Cu toxicity are related to mitochondrial dysfunction and damage, since Cu causes (i) a deficiency in the mitochondrial respiratory chain at the level of the Cu-dependent complex IV [7]; (ii) cross-linking of mitochondrial membranous proteins and subsequent contraction of the membrane [7]; (iii) oxidative stress [8] [9] [10] [11]; and (iv) increased acid sphingomyelinase (aSMase) activity [12]. "
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    ABSTRACT: We previously identified the Arabidopsis thaliana–derived decapeptide OSIP108, which increases tolerance of plants and yeast cells to oxidative stress. As excess copper (Cu) is known to induce oxidative stress and apoptosis, and is characteristic for the human pathology Wilson disease, we investigated the effect of OSIP108 on Cu-induced toxicity in yeast. We found that OSIP108 increased yeast viability in presence of toxic Cu concentrations, and decreased the prevalence of Cu-induced apoptotic markers. Next, we translated these results to the human hepatoma HepG2 cell line, demonstrating anti-apoptotic activity of OSIP108 in this cell line. In addition, we found that OSIP108 did not affect intracellular Cu levels in HepG2 cells, but preserved HepG2 mitochondrial ultrastructure. As Cu is known to induce acid sphingomyelinase activity of HepG2 cells, we performed a sphingolipidomic analysis of OSIP108-treated HepG2 cells. We demonstrated that OSIP108 decreased the levels of several sphingoid bases and ceramide species. Moreover, exogenous addition of the sphingoid base dihydrosphingosine abolished the protective effect of OSIP108 against Cu-induced cell death in yeast. These findings indicate the potential of OSIP108 to prevent Cu-induced apoptosis, possibly via its effects on sphingolipid homeostasis.
    Biochimica et Biophysica Acta (BBA) - Molecular Cell Research 06/2014; 1843(6). DOI:10.1016/j.bbamcr.2014.03.004 · 5.30 Impact Factor
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    • "insertion, deletion and splice site) (Lepori et al. 2012). Despite the vast number of mutations described, only a few mutations are prevalent in most ethnic groups (Ferenci 2006). In other words, the majority of the ATP7B mutations detected all over the world are rare. "
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    ABSTRACT: ATP7B is a copper-transporting ATPase that plays a key role in the regulation of copper homeostasis. Mutations in the ATP7B gene are causative for Wilson's disease, and recent reports have suggested that genetic variants are associated with susceptibility to Alzheimer's disease. Unfortunately, it is difficult to profile experimentally novel genetic variants in the ATP7B gene, because the human protein X-ray structure is not yet entirely understood. In order to investigate ATP7B non-synonymous substitutions, we used an in silico amino acid sequence-based approach. Specifically, we analyzed 337 ATP7B non-synonymous substitutions, which included Wilson's disease-causing mutations (DVs) and non Wilson's disease-causing variants (NDVs), with an algorithm that estimated a combined probability (cPdel) of an amino acidic change to be deleterious for the protein function. This approach appeared to reliably indentify the probability of DVs and NDVs to be deleterious and to profile still unknown gene variants. Specifically, after analyzing ATP7B protein domains with the cPdel method, we found results in line with the predicted-modeled domains and some new suggestions. In conclusion, a functional survey of amino acid changes in the ATP7B protein is provided herein, and we suggest that this bioinformatic method can furnish information about novel ATP7B mutations. Furthermore, the same approach can be applied to other uncharacterized proteins.
    Biology of Metals 11/2013; 27. DOI:10.1007/s10534-013-9686-3 · 2.69 Impact Factor
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    • "Analysis of eight exons (exons 2, 5, 8, 13, 14, 18, 19 and 20) would detect 82% of the mutations found in this population. The most frequent mutation identified was c.3207C4A, p.(His1069Gln), in exon 14, at a frequency of 19%, which is similar to the frequency previously reported in the UK but significantly lower than that found in other European countries (Ferenci, 2006). The next most common mutation was c.2305A4G, p. (Met769Val), in exon 8 found at a frequency of 6%, similar to that previously reported (Curtis et al., 1999). "
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    ABSTRACT: Previous studies have failed to identify mutations in the Wilson's disease gene ATP7B in a significant number of clinically diagnosed cases. This has led to concerns about genetic heterogeneity for this condition but also suggested the presence of unusual mutational mechanisms. We now present our findings in 181 patients from the United Kingdom with clinically and biochemically confirmed Wilson's disease. A total of 116 different ATP7B mutations were detected, 32 of which are novel. The overall mutation detection frequency was 98%. The likelihood of mutations in genes other than ATP7B causing a Wilson's disease phenotype is therefore very low. We report the first cases with Wilson's disease due to segmental uniparental isodisomy as well as three patients with three ATP7B mutations and three families with Wilson's disease in two consecutive generations. We determined the genetic prevalence of Wilson's disease in the United Kingdom by sequencing the entire coding region and adjacent splice sites of ATP7B in 1000 control subjects. The frequency of all single nucleotide variants with in silico evidence of pathogenicity (Class 1 variant) was 0.056 or 0.040 if only those single nucleotide variants that had previously been reported as mutations in patients with Wilson's disease were included in the analysis (Class 2 variant). The frequency of heterozygote, putative or definite disease-associated ATP7B mutations was therefore considerably higher than the previously reported occurrence of 1:90 (or 0.011) for heterozygote ATP7B mutation carriers in the general population (P < 2.2 × 10(-16) for Class 1 variants or P < 5 × 10(-11) for Class 2 variants only). Subsequent exclusion of four Class 2 variants without additional in silico evidence of pathogenicity led to a further reduction of the mutation frequency to 0.024. Using this most conservative approach, the calculated frequency of individuals predicted to carry two mutant pathogenic ATP7B alleles is 1:7026 and thus still considerably higher than the typically reported prevalence of Wilson's disease of 1:30 000 (P = 0.00093). Our study provides strong evidence for monogenic inheritance of Wilson's disease. It also has major implications for ATP7B analysis in clinical practice, namely the need to consider unusual genetic mechanisms such as uniparental disomy or the possible presence of three ATP7B mutations. The marked discrepancy between the genetic prevalence and the number of clinically diagnosed cases of Wilson's disease may be due to both reduced penetrance of ATP7B mutations and failure to diagnose patients with this eminently treatable disorder.
    Brain 03/2013; 136(5). DOI:10.1093/brain/awt035 · 10.23 Impact Factor
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