Molecular mechanism of copper transport in Wilson disease.

Fatemi, Negah; Sarkar, Bibudhendra

doi:10.1289/ehp.02110s5695

Cited by 40 publications

(22 citation statements)

References 55 publications

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“…Since the SNPs are in linkage disequilibrium (data not shown), either could be the functional SNP or both could be serving as markers of additional functional SNPs in ATP7B . While, to our knowledge, this gene has not previously been studied with regards to Hg toxicokinetics, the protein is known to have affinity for several metals, including Hg [30], and whether ATP7B can serve as a Hg transporter in humans merits future study.…”

Section: Discussionmentioning

confidence: 99%

Genetic polymorphisms are associated with hair, blood, and urine mercury levels in the American Dental Association (ADA) study participants

Parajuli

Goodrich²,

Chou

et al. 2016

Environmental Research

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Background/Aims Mercury (Hg) is a potent toxicant of concern to the general public. Recent studies suggest that several genes that mediate Hg metabolism are polymorphic. We hypothesize that single nucleotide polymorphisms (SNPs) in such genes may underline inter-individual differences in exposure biomarker concentrations. Methods Dental professionals were recruited during the American Dental Association (ADA) 2012 Annual Meeting. Samples of hair, blood, and urine were collected for quantifying Hg levels and genotyping (88 SNPs in classes relevant to Hg toxicokinetics including glutathione metabolism, selenoproteins, metallothioneins, and xenobiotic transporters). Questionnaires were administrated to obtain information on demographics and sources of Hg exposure (e.g., fish consumption and use of dental amalgam). Here, we report results for 380 participants with complete genotype and Hg biomarker datasets. ANOVA and linear regressions were used for statistical analysis. Results Mean (geometric) Hg levels in hair (hHg), blood (bHg), urine (uHg), and the average estimated Hg intake from fish were 0.62μg/g, 3.75μg/L, 1.32μg/L, and 0.12μg/kg body weight/day, respectively. Out of 88 SNPs successfully genotyped, Hg biomarker levels differed by genotype for 25 SNPs, one of which remained significant following Bonferroni correction in ANOVA. When the associations between sources of Hg exposure and SNPs were analyzed with respect to Hg biomarker concentrations, 38 SNPs had significant main effects and/or gene-Hg exposure source interactions. Twenty-five, 23, and four SNPs showed significant main effects and/or interactions for hHg, bHg, and uHg levels, respectively (p<0.05), and six SNPs (in GCLC, MT1M, MT4, ATP7B, and BDNF) remained significant following Bonferroni correction. Conclusion The findings suggest that polymorphisms in environmentally-responsive genes can influence Hg biomarker levels. Hence, consideration of such gene-environment factors may improve the ability to assess the health risks of Hg more precisely.

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Section: Discussionmentioning

confidence: 99%

Genetic polymorphisms are associated with hair, blood, and urine mercury levels in the American Dental Association (ADA) study participants

Parajuli

Goodrich²,

Chou

et al. 2016

Environmental Research

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“…Molecular genetic testing for ATP7B mutations is available in clinic, which is applied for diagnosis/prediction of a disease caused by ATP7B mutations, Wilson's disease. 22 A study in preschool kids found that rs6900017 of VEGFA gene was associated with their lung function at school age, but not at birth that suggested a potential function of VEGFA variants in lung development. 23 Although no studies of the function of rs879825 and rs9369421 so far, they are in high linkage disequilibrium with rs6900017 as we found in our study.…”

Section: Discussionmentioning

confidence: 99%

Carboplatin/taxane-induced gastrointestinal toxicity: a pharmacogenomics study on the SCOTROC1 trial

Winham

Hoskins

et al. 2015

Pharmacogenomics J

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Carboplatin/taxane combination is first-line therapy for ovarian cancer. However, patients can encounter treatment delays, impaired quality of life, even death because of chemotherapy-induced gastrointestinal (GI) toxicity. A candidate gene study was conducted to assess potential association of genetic variants with GI toxicity in 808 patients who received carboplatin/taxane in the Scottish Randomized Trial in Ovarian Cancer 1 (SCOTROC1). Patients were randomized into discovery and validation cohorts consisting of 404 patients each. Clinical covariates and genetic variants associated with grade III/IV GI toxicity in discovery cohort were evaluated in replication cohort. Chemotherapy-induced GI toxicity was significantly associated with seven single-nucleotide polymorphisms in the ATP7B, GSR, VEGFA and SCN10A genes. Patients with risk genotypes were at 1.53 to 18.01 higher odds to develop carboplatin/taxane-induced GI toxicity (P<0.01). Variants in the VEGF gene were marginally associated with survival time. Our data provide potential targets for modulation/inhibition of GI toxicity in ovarian cancer patients.

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“…Specifically, the N-terminal metal-binding domain (MBD) is composed of six copper-binding sites, each with the conserved sequence motif GMXCXXC (Fatemi and Sarkar, 2002; Sazinsky et al, 2006). These MBDs play a central role in accepting copper from copper chaperone ATOX1 through protein–protein interactions.…”

Section: Atp7b (P-type Atpase) Protein Structure and Functionmentioning

confidence: 99%

The genetics of Wilson disease

Chang

Hahn

2017

Handbook of Clinical Neurology

117

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Wilson disease is an autosomal-recessive disorder of hepatocellular copper deposition caused by pathogenic variants in the copper-transporting gene, ATP7B. Early detection and treatment are critical to prevent lifelong neuropsychiatric, hepatic, and systemic disabilities. Due to the marked heterogeneity in age of onset and clinical presentation, the diagnosis of Wilson disease remains challenging to physicians today. Direct sequencing of the ATP7B gene is the most sensitive and widely used confirmatory testing method, and concurrent biochemical testing improves diagnostic accuracy. More than 600 pathogenic variants in ATP7B have been identified, with single-nucleotide missense and nonsense mutations being the most common, followed by insertions/deletions, and, rarely, splice site mutations. The prevalence of Wilson disease varies by geographic region, with higher frequency of certain mutations occurring in specific ethnic groups. Wilson disease has poor genotype–phenotype correlation, although a few possible modifiers have been proposed. Improving molecular genetic studies continue to advance our understanding of the pathogenesis, diagnosis, and screening for Wilson disease.

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Molecular mechanism of copper transport in Wilson disease.

Cited by 40 publications

References 55 publications

Genetic polymorphisms are associated with hair, blood, and urine mercury levels in the American Dental Association (ADA) study participants

Genetic polymorphisms are associated with hair, blood, and urine mercury levels in the American Dental Association (ADA) study participants

Carboplatin/taxane-induced gastrointestinal toxicity: a pharmacogenomics study on the SCOTROC1 trial

The genetics of Wilson disease

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