Cellular Function of ATP7B (Wilson ATPase)

Polishchuk, Roman

doi:10.1016/b978-0-12-810532-0.00006-9

Cited by 2 publications

(1 citation statement)

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“…Wilson’s disease (WD) is a rare autosomal recessive disorder of copper metabolism caused by pathogenic variants of the human ATP7B gene encoding the ATP7B protein, which is a copper-transporting P-type ATPase. , The approximately 160 kDa membrane protein contains a large N-terminal domain consisting of six metal-binding domains, eight transmembrane segments, an adenosine triphosphate (ATP)-binding domain, and a soluble C-terminal tail. − In the hepatocyte, ATP7B transports copper from the cytosol into the Golgi apparatus and mediates either the incorporation of copper into ceruloplasmin or the excretion of excess copper into the bile. , To accomplish its copper-transport function, the protein depends critically on its ability to use the energy gained by ATP hydrolysis …”

Section: Introductionmentioning

confidence: 99%

Computing the Pathogenicity of Wilson’s Disease ATP7B Mutations: Implications for Disease Prevalence

Tang

Sandahl

Ott

et al. 2019

J. Chem. Inf. Model.

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Genetic variations in the gene encoding the copper-transport protein ATP7B are the primary cause of Wilson's disease. Controversially, clinical prevalence seems much smaller than prevalence estimated by genetic screening tools, causing fear that many people are undiagnosed although early diagnosis and treatment is essential. To address this issue, we benchmarked 16 state-of-the-art computational disease-prediction methods against established data of missense ATP7B mutations. Our results show that the quality of the methods vary widely. We show the importance of optimizing the threshold of the methods used to distinguish pathogenic from non-pathogenic mutations against data of clinically confirmed pathogenic and non-pathogenic mutations. We find that most methods use thresholds that predict too many ATP7B mutations to be pathogenic. Thus, our findings explain the current controversy on Wilson's disease prevalence, because meta analysis and text search methods include many computational estimates that lead to higher disease prevalence than clinically observed. Since proteins and diseases differ widely, a one-size-fits-all threshold cannot distinguish efficiently pathogenic and non-pathogenic mutations, as shown here. We also show that amino acid changes with small evolutionary substitution probability, mainly due to amino acid volume, are more associated with disease, implying a pathological effect on the conformational state of the protein, which could affect copper transport or ATP recognition and hydrolysis. These findings may be a first step towards a more quantitative genotype-phenotype relationship of Wilson's disease.

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Section: Introductionmentioning

confidence: 99%

Computing the Pathogenicity of Wilson’s Disease ATP7B Mutations: Implications for Disease Prevalence

Tang

Sandahl

Ott

et al. 2019

J. Chem. Inf. Model.

View full text Add to dashboard Cite

show abstract

Benchmarking Computational Methods for Estimating the Pathogenicity of Wilson’s Disease Mutations

Tang

Sandahl

Ott

et al. 2019

Preprint

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Genetic variations in the gene encoding the copper-transport protein ATP7B are the primary cause of Wilson's disease. Controversially, clinical prevalence seems much smaller than prevalence estimated by genetic screening tools, causing fear that many people are undiagnosed although early diagnosis and treatment is essential. To address this issue, we benchmarked 16 state-of-the-art computational disease-prediction methods against established data of missense ATP7B mutations.Our results show that the quality of the methods vary widely. We show the importance of optimizing the threshold of the methods used to distinguish pathogenic from non-pathogenic mutations against data of clinically confirmed pathogenic and non-pathogenic mutations. We find that most methods use thresholds that predict too many ATP7B mutations to be pathogenic. Thus, our findings explain the current controversy on Wilson's disease prevalence, because meta analysis and text search methods include many computational estimates that lead to higher disease prevalence than clinically observed. Since proteins differ widely, a one-size-fits-all threshold for all proteins cannot distinguish efficiently pathogenic and non-pathogenic mutations, as shown here. We also show that amino acid changes with small evolutionary substitution probability, mainly due to amino acid volume, are more associated with disease, implying a pathological effect on the conformational state of the protein, which could affect copper transport or ATP recognition and hydrolysis. These findings may be a first step towards a more quantitative genotype-phenotype relationship of Wilson's disease.

show abstract

Cellular Function of ATP7B (Wilson ATPase)

Cited by 2 publications

References 76 publications

Computing the Pathogenicity of Wilson’s Disease ATP7B Mutations: Implications for Disease Prevalence

Computing the Pathogenicity of Wilson’s Disease ATP7B Mutations: Implications for Disease Prevalence

Benchmarking Computational Methods for Estimating the Pathogenicity of Wilson’s Disease Mutations

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