Disease relevance of ATP7A

• The present report is the first to describe an ATP7A truncation that results in OHS rather than in Menkes disease [1].
• Defects in a similar gene, the copper transporting ATPase ATP7B, result in Wilson disease [2].
• Inactivation of ATP7B or related ATP7A leads to severe neurodegenerative disorders, whereas their overexpression contributes to cancer cell resistance to chemotherapeutics [3].
• ATP7A and ATP7B appear to be able to modulate the toxicity of the Pt that accumulates in DNA following exposure to JM118 [4].
• Here, we show that, of five cisplatin-resistant cell lines, only one (SR2) exhibited substantial reduction in hCtr1 expression as compared with that in its sensitive line small cell lung cancers (SCLC), whereas copper efflux transporters ATP7A and ATP7B were not significantly altered [5].

Psychiatry related information on ATP7A

• Developmental changes in the expression of ATP7A during a critical period in postnatal neurodevelopment [6].
• The MC1-induced anti-Id response (Ab-3) in both mice and rabbits expressed a similar Id with the Ab-1, which is not normally expressed in the anti-gp41 peptide antibody response induced by the nominal antigen in Balb/c mice and in rabbits [7].
• CONCLUSION: Exposure variables, chronic diseases, alcohol consumption, and sedative use contribute to educational inequalities in traffic and OHS injuries resulting in hospital admission [8].
• METHODS: Data came from two contemporaneous surveys, the National Comorbidity Survey (NCS; N=6780) and the Mental Health Supplement of the Ontario Health Survey (OHS-MHS; N=7001) [9].
• This study examined whether conformational changes detected by antibodies MC1 and TG3 represent early abnormalities in the disease process by assessing their presence at different stages of dementia in multiple brain regions [10].

High impact information on ATP7A

• Human Menkes disease and the murine Mottled phenotype are X-linked diseases that result from copper deficiency due to mutations in a copper-effluxing ATPase, designated ATP7A [11].
• Mutations in the genes encoding the major fibrillar collagen types I and III have been demonstrated in EDS types VII and IV, respectively, while mutations in the lysyl hydroxylase and ATP7A genes, with roles in collagen cross-linking, are responsible for EDS types VI and IX [12].
• 3. On yeast artificial chromosomes from this region we have identified a sequence, similar to that coding for the proposed copper binding regions of the putative ATPase gene (MNK) defective in Menkes disease [13].
• The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene [14].
• Among these, expression analysis of UHRF1, ATP7A, and aldehyde oxidase 1 in combination could potentially provide a useful additional diagnostic tool for fine-needle aspirated or cytological specimens obtained during endoscopic investigations [15].

Chemical compound and disease context of ATP7A

• The influence of these transporters on the pharmacodynamics of cisplatin, carboplatin, and oxaliplatin was investigated using human Menkes' disease fibroblasts (Me32a) that do not express either transporter and sublines molecularly engineered to express either ATP7A (MeMNK) or ATP7B (MeWND) [16].
• Increased expression of the copper efflux transporter ATP7A mediates resistance to cisplatin, carboplatin, and oxaliplatin in ovarian cancer cells [17].
• We describe a child with classical Menkes disease with a novel ATP7A mutation, intractable seizures, severe hypotonia and developmental delay, hypopigmentation of the skin and hair, and failure to thrive, who was treated with daily subcutaneous copper histidine injections for 2(1/2) years, beginning at 15 months of age [18].
• We have pursued equilibrium binding experiments to examine the affinity of Ncd for microtubules in the presence of the ATP nonhydrolyzable analog 5'-adenylyl-beta, gamma-imidodiphosphate (AMP-PNP), ADP, or ADP + Pi using both dimeric (MC1) and monomeric (MC6) Ncd constructs expressed in Escherichia coli [19].

Biological context of ATP7A

• These findings indicate that the presence of barely detectable amounts of correctly spliced ATP7A transcript is sufficient to permit the development of the milder OHS phenotype, as opposed to classic MD [20].
• More than 150 point mutations have now been identified in the ATP7A gene [20].
• In contrast to previously reported cases of OHS, we describe a case of OHS in which, because of a frameshift mutation, no normal ATP7A is produced [1].
• In this study we show that ATP7A is internalized by a novel pathway that is independent of clathrin-mediated endocytosis [21].
• ATP7A is a P-type ATPase involved in copper(I) homeostasis in humans [22].

Anatomical context of ATP7A

• It has been demonstrated that the dileucine motif L1487L1488 functions as an endocytic signal for ATP7A cycling between the TGN and the plasma membrane [1].
• Data suggest that steady-state localization of ATP7A to the trans-Golgi network (TGN) is necessary for proper activity of lysyl oxidase, which is the predominant cuproenzyme whose activity is deficient in OHS and which is essential for maintenance of connective-tissue integrity [1].
• These findings define a novel route required for ATP7A internalization and delivery to endosomes [21].
• The Menkes disease gene encodes a P-type transmembrane ATPase (ATP7A) that translocates cytosolic copper ions across intracellular membranes of compartments along the secretory pathway [21].
• These findings indicate that endoplasmic reticulum localization only of a variant ATP7A protein is insufficient to effect normal copper transport [23].

Associations of ATP7A with chemical compounds

• We have generated polyclonal antibodies against the amino-terminal third of the Menkes protein (ATP7A; MNK) by immunizing rabbits with a histidine-tagged MNK fusion construct containing metal-binding domains 1-4 [24].
• Modulation of the cellular pharmacology of cisplatin and its analogs by the copper exporters ATP7A and ATP7B [16].
• The 2008 and 2008/JM118 cells did not differ in their uptake or efflux of (64)Cu, expression of Cu efflux transporters ATP7A or ATP7B or their glutathione content [25].
• A point mutation (T to C) that results in substitution of proline for serine in a putative eighth transmembrane domain of the ATP7A was identified [26].
• Compared to ATP7A, the rat transcript coded for an additional alanine (A446) in the heavy metal binding (Hmb) domain and showed a 34 bp gap in the 3' UTR [27].

Physical interactions of ATP7A

• ATOX1 is a cytoplasmic copper chaperone that interacts with the copper-binding domain of the membrane copper transporters ATP7A and ATP7B [28].
• We propose a change in name for this protein from PISP (plasma membrane calcium ATPase-interacting single-PDZ protein) to AIPP1 (ATPase-interacting PDZ protein) and suggest that it represents the protein that interacts with the class I PDZ binding motif identified at the ATP7A C terminus [29].

Other interactions of ATP7A

• On Western blot analysis all three resistant lines exhibited increased expression of one or the other of the two copper export pumps (ATP7A or ATP7B) with no change in the HAH1 chaperone [30].
• Atx1 and ATOX1 both contain an MXCXXC motif that is also present in Ccc2 (two motifs) and ATP7A/B (six motifs) [31].
• Although delivery of copper to lumenal cuproproteins like PAM involves ATP7A, lumenal chaperones may not be required [32].
• In contrast, expression of a constitutively active mutant of the Rac1 GTPase inhibits plasma membrane internalization of both the ATP7A and transferrin receptor transmembrane proteins [21].
• Copper-dependent interaction of dynactin subunit p62 with the N terminus of ATP7B but not ATP7A [33].

Analytical, diagnostic and therapeutic context of ATP7A

• Sequence analysis revealed that the 1.9 kb cDNA encoded one of the six Cu-binding sites and two of the eight transmembrane domains of ATP7A [34].
• We studied the effect of copper perfusion of an isolated segment of the jejunum of ATP7A transgenic mice on the intracellular distribution of ATP7A by immunofluorescence of frozen sections [35].
• In the present study, we report the use of three fast and reliable polymerase chain reaction (PCR)-based methods for the identification of partial ATP7A deletions in Menkes disease patients [36].
• We have previously demonstrated identification of partial ATP7A deletions in patients by Southern blot analysis [36].
• The study was carried out through titrations involving HAH1 and either the second or the fifth soluble domains of ATP7A (MNK2 and MNK5, respectively), in the presence of copper(I) [37].

References