Single nucleotide polymorphisms in the human <i>ATP7B</i> gene modify the properties of the ATP7B protein

McCann, Courtney J.; Jayakanthan, Samuel; Siotto, Mariacristina; Yang, Nan; Osipova, M. A.; Squitti, Rosanna; Lutsenko, Svetlana

doi:10.1039/c9mt00057g

Cited by 15 publications

(14 citation statements)

References 57 publications

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“…Copper disturbance in AD can be described by a loss of functional copper from protein-bound pools that reduces energy production and oxidative stress control, and a gain of redox-toxic function that is described by a bigger pool of copper loosely bound to proteins [ 16 ]. Non-ceruloplasmin copper increases the susceptibility to AD approximately threefold [ 42 , 43 ] and it is also associated with a higher frequency of specific variants of the ATP7B gene [ 45 , 46 , 47 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 ] ( Table 1 ). The gene variants rs1061472 and rs732774 of ATP7B are single nucleotide polymorphisms (SNPs) that modify properties of ATPase7B protein and are associated with a higher risk of AD and with the presence of a higher fraction of non-ceruloplasmin copper in serum [ 38 , 55 , 58 ].…”

Section: Alzheimer’s Disease and Coppermentioning

confidence: 99%

“…In the previous section of this paper, we have given an overview of the scientific evidence sustaining that excessive use of copper in agriculture that can lead to severe soil pollution. Through the food chain, copper may accumulate in the human body, causing health problems in those people with a predisposition to copper imbalance, as those carriers of the ATP7B functional SNPs rs1061472 A > G and rs 732774 G > A [ 53 ].…”

Section: Agroecological Strategies To Reduce the Use Of Copper Inmentioning

confidence: 99%

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Agricultural Use of Copper and Its Link to Alzheimer’s Disease

et al. 2020

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Copper is an essential nutrient for plants, animals, and humans because it is an indispensable component of several essential proteins and either lack or excess are harmful to human health. Recent studies revealed that the breakdown of the regulation of copper homeostasis could be associated with Alzheimer’s disease (AD), the most common form of dementia. Copper accumulation occurs in human aging and is thought to increase the risk of AD for individuals with a susceptibility to copper exposure. This review reports that one of the leading causes of copper accumulation in the environment and the human food chain is its use in agriculture as a plant protection product against numerous diseases, especially in organic production. In the past two decades, some countries and the EU have invested in research to reduce the reliance on copper. However, no single alternative able to replace copper has been identified. We suggest that agroecological approaches are urgently needed to design crop protection strategies based on the complementary actions of the wide variety of crop protection tools for disease control.

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Section: Alzheimer’s Disease and Coppermentioning

confidence: 99%

Section: Agroecological Strategies To Reduce the Use Of Copper Inmentioning

confidence: 99%

Agricultural Use of Copper and Its Link to Alzheimer’s Disease

et al. 2020

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“…Therefore, the two frequent core promoter polymorphisms are candidate genetic modifiers of Wilson disease phenotype. The marked variability of the Wilson disease clinical phenotype that is even observed in carriers of the same mutation(s) has not yet been explained; several modifying influences have been suggested to contribute: besides environmental factors, epigenetic and transgenetic effectors and protein interactions of different missense variants are in the list 40 , 43 , 44 .…”

Section: Discussionmentioning

confidence: 99%

Investigation of the Wilson gene ATP7B transcriptional start site and the effect of core promoter alterations

Höflich

Brieger

Zeuzem

et al. 2021

Sci Rep

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Pathogenic genetic variants in the ATP7B gene cause Wilson disease, a recessive disorder of copper metabolism showing a significant variability in clinical phenotype. Promoter mutations have been rarely reported, and controversial data exist on the site of transcription initiation (the core promoter). We quantitatively investigated transcription initiation and found it to be located in immediate proximity of the translational start. The effects human single-nucleotide alterations of conserved bases in the core promoter on transcriptional activity were moderate, explaining why clearly pathogenic mutations within the core promoter have not been reported. Furthermore, the core promoter contains two frequent polymorphisms (rs148013251 and rs2277448) that could contribute to phenotypical variability in Wilson disease patients with incompletely inactivating mutations. However, neither polymorphism significantly modulated ATP7B expression in vitro, nor were copper household parameters in healthy probands affected. In summary, the investigations allowed to determine the biologically relevant site of ATP7B transcription initiation and demonstrated that genetic variations in this site, although being the focus of transcriptional activity, do not contribute significantly to Wilson disease pathogenesis.

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“…WD is a monogenetic disorder with a remarkable variety of both mutations and manifestations of disease. Previous studies have identified ATP7B mutations in different domains of the protein that had a negative impact on ATP7B stability 13 , loss of Cu-transport activity 14 , ER retention 15 , and inability to traffic from the TGN to vesicles in response to Cu elevation 16,17 . However, establishing clear genotype-phenotype correlations in WD has proven difficult.…”

Section: Discussionmentioning

confidence: 99%

“…A previously characterized catalytically inactive mutant D1027A 15 has been used as a negative control in the tyrosinase activity assay. Pigment intensity and area were quantified using Image-J software 16 , and total signal intensity was calculated using the equation …”

Section: Methodsmentioning

confidence: 99%

Analysis of Wilson disease mutations revealed that interactions between different ATP7B mutants modify their properties

Roy

McCann²,

Ralle

et al. 2020

Sci Rep

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Wilson disease (WD) is an autosomal-recessive disorder caused by mutations in the copper (cu)transporter ATP7B. Thus far, studies of WD mutations have been limited to analysis of ATP7B mutants in the homozygous states. However, the majority of WD patients are compound-heterozygous, and how different mutations on two alleles impact ATP7B properties is unclear. We characterized five mutations identified in Indian WD patients, first by expressing each alone and then by co-expressing two mutants with dissimilar properties. Mutations located in the regulatory domains of ATP7B-A595T, S1362A, and S1426I-do not affect ATP7B targeting to the trans-Golgi network (TGN) but reduce its Cu-transport activity. The S1362A mutation also inhibits Cu-dependent trafficking from the TGN. The G1061E and G1101R mutations, which are located within the ATP-binding domain, cause ATP7B retention in the endoplasmic reticulum, inhibit Cu-transport, and lower ATP7B protein abundance. Co-expression of the A595T and G1061E mutations, which mimics the compoundheterozygous state of some WD patients, revealed an interaction between these mutants that altered their intracellular localization and trafficking under both low and high Cu conditions. These findings highlight the need to study WD variants in both the homozygous and compound-heterozygous states to better understand the genotype-phenotype correlations and incomplete penetrance observed in WD. Copper (Cu) is a redox-active metal that is indispensable for human growth and development. Cu is required for the activity of several enzymes, including cytochrome c oxidase, Cu/Zn-dependent superoxide dismutases, tyrosinase, dopamine-β-hydroxylase, ceruloplasmin, and peptidyl-α-monooxygenase 1. In order to ensure an adequate supply of Cu without toxic accumulation, Cu homeostatic mechanisms are tightly regulated. Either Cu deficiency or overabundance is associated with pathologic changes and disease, such as, Menkes disease or Wilson disease (WD), respectively 2,3. WD is a genetic disorder caused by mutations in the Cu-transporter ATP7B that causes abnormal deposition of Cu in the liver and the brain 4. WD has a spectrum of hepatic and neurological manifestations, along with a broad range of disease onsets 5. The mechanisms behind this variability remain poorly understood. Studies of WD patients identified over 600 ATP7B mutations 6 and revealed the diverse effects of mutations on the functional and cellular properties of the ATP7B protein. Efforts to link different phenotypic presentations of WD to specific ATP7B mutations have not produced strong correlations and have sometimes led to conflicting results 7. High prevalence of compound-heterozygous mutations further complicates the task of genotype-phenotype correlation 8 .

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Single nucleotide polymorphisms in the human ATP7B gene modify the properties of the ATP7B protein

Abstract: Two single nucleotide polymorphisms in Cu-transporter ATP7B alter protein properties and copper status in humans.

Cited by 15 publications

References 57 publications

Agricultural Use of Copper and Its Link to Alzheimer’s Disease

Agricultural Use of Copper and Its Link to Alzheimer’s Disease

Investigation of the Wilson gene ATP7B transcriptional start site and the effect of core promoter alterations

Analysis of Wilson disease mutations revealed that interactions between different ATP7B mutants modify their properties

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