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: 4.82). 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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    • "As a result, excess copper accumulates in many organs and tissues, particularly the liver and brain. The disease is characterised by the presence of liver disease, neurological and psychiatric symptoms (Ferenci 2006; Weiss 1999). Osteoporosis is a metabolic bone disease characterised by an imbalance between bone formation and resorption, that leads to a net decrease in bone mass with reduced bone strength and increased susceptibility to fracture (Gielen et al 2011). "
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    ABSTRACT: We compared the bone mineral density (BMD) of adult Wilson disease (WD) patients (n = 148), with an age- and gender-matched healthy control population (n = 148). Within the WD cohort, correlations of BMD with WD disease parameters, lab results, type of treatment and known osteoporosis risk factors were analysed. Hip and lumbar spine absolute BMD and T-score were measured by dual-energy X-ray absorptiometry. Osteoporosis and osteopenia were defined as a T-score ≤ -2.5, and between -1 and -2.5, respectively. There were significantly more subjects with abnormal T-scores in the WD population (58.8 %) than in the control population (45.3 %) (χ(2) = 6.65, df = 2, p = 0.036), as there were 50.0 % osteopenic and 8.8 % osteoporotic WD patients, vs. 41.2 % and 4.1 %, respectively, in the controls. Especially L2-L4 spine BMD measurements (BMD and T-scores) differed significantly between the WD population and matched controls. L2-L4 spine BMD for WD patients was on average 0.054 g/cm(2) (5.1 %) lower than in matched normal controls (0.995 ± 0.156 vs 1.050 ± 0.135; p = 0.002). We found no significant correlation between BMD values and any of the WD disease parameters (e.g. the severity of liver disease), lab results, type of treatment or known osteoporosis risk factors. Duration of D-penicillamine treatment was negatively correlated with femoral BMD value, but in a clinically irrelevant manner, compared to age and gender. Importantly, BMD remained significantly lower in WD patients (n = 89) vs. controls after excluding WD patients with cirrhosis (p = 0.009). Our study suggests that WD is intrinsically associated with bone demineralisation.
    Journal of Inherited Metabolic Disease 02/2015; 38(5). DOI:10.1007/s10545-015-9815-y · 3.37 Impact Factor
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    • "ATP7B plays an essential role in Cu excretion from hepatocytes into bile and for mobilization of ceruloplasmin-bound Cu from hepatocytes into the serum (Huster, 2010). ATP7B mutations in WD patients cause accumulation of Cu in the liver (Ferenci, 2006) that can result in acute liver failure (ALF) or cirrhosis (Ala et al., 2007). Furthermore , elevated intracellular Cu levels cause degeneration of neuronal cells, which is also a WD-characteristic (Loudianos and Gitlin, 2000; Huster, 2010). "
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    ABSTRACT: Background Wilson disease (WD) is caused by accumulation of excess copper (Cu) due to a mutation in the gene encoding the liver Cu transporter ATP7B, and is characterized by acute liver failure or cirrhosis and neuronal cell death. We investigated the effect of OSIP108, a plant derived decapeptide that prevents Cu-induced apoptosis in yeast and human cells, on Cu-induced toxicity in various mammalian in vitro models relevant for WD and in a Cu-toxicity zebrafish larvae model applicable to WD. Methods The effect of OSIP108 was evaluated on viability of various cell lines in presence of excess Cu, on liver morphology of a Cu-treated zebrafish larvae strain that expresses a fluorescent reporter in hepatocytes, and on oxidative stress levels in wild type AB zebrafish larvae. Results OSIP108 increased viability of Cu-treated CHO cells transgenically expressing ATP7B and the common WD-causing mutant ATP7BH1069Q, but also viability of Cu-treated human glioblastoma U87 cells. Aberrancies in liver morphology of Cu-treated zebrafish larvae were observed, which were further confirmed as Cu-induced hepatotoxicity by liver histology. Injections of OSIP108 into Cu-treated zebrafish larvae significantly increased the amount of larvae with normal liver morphology, and decreased Cu-induced production of reactive oxygen species. Conclusions OSIP108 prevents Cu-induced toxicity in in vitro models and in a Cu-toxicity zebrafish larvae model applicable to WD. General significance All the above data indicate the potential of OSIP108 as a drug lead for further development as a novel WD treatment.
    Toxicology and Applied Pharmacology 10/2014; 280(2). DOI:10.1016/j.taap.2014.08.005 · 3.71 Impact Factor
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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 · 5.02 Impact Factor
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