Two forms of Wilson disease protein produced by alternative splicing are localized in distinct cellular compartments

Yang, Xiao‐Li; Miura, Naoyuki; Kawarada, Yoshihiko; Terada, Kunihiko; Petrukhin, Konstantin; Gilliam, T. Conrad; Sugiyama, Toshihiro

doi:10.1042/bj3260897

Cited by 90 publications

(60 citation statements)

References 32 publications

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“…This alternative splice variant has a normal read ing frame and gives rise to a shorter protein. Yang et al have shown that this protein is mainly present in the cytosol whereas the normal ATP7B is in the trans-Golgi apparatus [44]. These alternative splice variants of ATP7B are expressed in the brain [45] and could be an explanation for differences in central nervous system manifestations, as tentatively shown in this study.…”

Section: Discussionsupporting

confidence: 53%

Psychopathology and personality traits in patients with treated Wilson disease grouped according to gene mutations

Portala¹,

Waldenström²,

Knorring³

et al. 2008

Upsala Journal of Medical Sciences

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Wilson disease (WD) is a recessively inherited copper storage disorder mainly affecting liver and brain. Genotype/phenotype correlations have been report ed but as yet not regarding psychic symptoms. Our aim was to investigate if a correlation might exist between genotype and phenotype concerning psy cho pathology and/or personality traits in patients with treated WD. Nine homozygous and three compound heterozygous Swedish patients were retrospectively investigated, representing four different mutation set tings. Psychopathological symptoms were studied using the Comprehensive Psychopathological Rating Scale (CPRS), personality traits using the Karo lin ska Scales of Personality (KSP) and mutations were analyzed by manifold sequencing. Psychopathological symptoms: Patients with the Trp779Stop mutation had the lowest scores on the total CPRS, due to less pronounced reported CPRS items, as compared to the other three groups of patients. Compound heterozygotes for the His1069Gln/ Arg1319Stop mutation show ed the highest total CPRS scores. Personality traits: Patients homozygous for the Trp779Stop and the Thr977Met mutations had high scores on Psycho pathy related scales whereas patients with His1069Gln/Arg1319Stop mutations had the lowest scores on these scales. Serum ceruloplasmin levels were undetectable in all patients with the Trp779Stop and Thr977Met mutations. The results show a trend towards a genotype/phenotype correlation regarding psychopathological symptoms and personality traits in treated patients with WD. If replicable, these results might contribute to the elucidation of the possible clinical importance of functionally deleterious gene mutations in WD psychopathology and personality traits.

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Section: Discussionsupporting

confidence: 53%

Psychopathology and personality traits in patients with treated Wilson disease grouped according to gene mutations

Portala¹,

Waldenström²,

Knorring³

et al. 2008

Upsala Journal of Medical Sciences

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“…The Menkes protein is a single-chain 178-kDa polypeptide that is localized to the trans-Golgi network and undergoes a copper-dependent relocalization in human and rodent cell lines (8 -10). Recent studies have revealed similar findings for the homologous Wilson disease ATPase (11,12), suggesting a common mechanism for copper transport by these proteins into the secretory pathway of the cell.…”

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confidence: 50%

Functional Expression of the Menkes Disease Protein Reveals Common Biochemical Mechanisms Among the Copper-transporting P-type ATPases

Payne

Gitlin

1998

Journal of Biological Chemistry

149

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Menkes disease is a fatal neurodegenerative disorder of childhood caused by the absence or dysfunction of a putative P-type ATPase encoded on the X chromosome. To elucidate the function of the Menkes disease protein, a plasmid containing the open reading frame of the human Menkes disease gene was constructed and used to transform a strain of Saccharomyces cerevisiae deficient in CCC2, the yeast Menkes/Wilson disease gene homologue. ccc2⌬ yeast are deficient in copper transport into the secretory pathway, and expression of a wild type human Menkes cDNA complemented this defect, as evidenced by the restoration of copper incorporation into the multicopper oxidase Fet3p. Site-directed mutagenesis demonstrated the essential role of four specific amino acids in this process, including a conserved histidine, which is the site of the most common disease mutation in the homologous Wilson disease protein. The expression of Menkes cDNAs with successive mutations of the conserved cysteine residues in the six aminoterminal MXCXXC metal binding domains confirmed the essential role of these cysteine residues in copper transport but revealed that each of these domains is not functionally equivalent. These data demonstrate that the Menkes disease protein functions to deliver copper into the secretory pathway of the cell and that this process involves biochemical mechanisms common to previously characterized members of this P-type ATPase family.

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“…The sections were incubated with 100-folddiluted monoclonal antibody against the NH 2 -terminal region of ATP7B, which includes the six copper-binding domains (amino acids 21 to 623; see Ref. 22) for 15 h at 4°C. After rinsing with PBS, the sections were incubated with biotinylated horse anti-mouse IgG at 1:200 with 1.5% normal horse serum for 30 min at room temperature.…”

Section: Methodsmentioning

confidence: 99%

Copper‐transporting P‐Type Adenosine Triphosphatase (ATP7B) Is Expressed in Human Breast Carcinoma

Kanzaki

Toi

Neamati

et al. 2002

Japanese Journal of Cancer Research

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This is the first report to show that a copper-transporting P-type adenosine triphosphatase, ATP7B, is expressed in certain breast carcinomas, and a priori knowledge of its expression is important for the choice of therapy. We investigated the hypothesis that ATP7B, which was shown to be associated with cisplatin resistance in vitro, is expressed in certain breast carcinomas. To test this hypothesis, ATP7B expression and protein level were examined in 41 breast carcinomas using RT-PCR and immunohistochemistry. ATP7B gene/protein could be detected in 22.0% (9/41) of breast carcinomas and ATP7B gene expression was correlated well with the protein expression. In nine ATP7B-positive tumors, adjacent normal breast tissue was similarly analyzed, revealing that ATP7B is upregulated in breast carcinoma. ATP7B gene expression in poorly differentiated carcinoma was significantly higher than that in well-/moderately differentiated carcinoma (P = = = =0.012).Furthermore, we found no association between the ATP7B gene/protein expression and that of MDR1, MRP1, LRP and BCRP. These findings suggested that ATP7B gene expression might be a chemoresistance marker for cisplatin in patients with poorly differentiated breast carcinoma.

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Two forms of Wilson disease protein produced by alternative splicing are localized in distinct cellular compartments

Cited by 90 publications

References 32 publications

Psychopathology and personality traits in patients with treated Wilson disease grouped according to gene mutations

Psychopathology and personality traits in patients with treated Wilson disease grouped according to gene mutations

Functional Expression of the Menkes Disease Protein Reveals Common Biochemical Mechanisms Among the Copper-transporting P-type ATPases

Copper‐transporting P‐Type Adenosine Triphosphatase (ATP7B) Is Expressed in Human Breast Carcinoma

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