Disease relevance of Atp7a

• Menkes kinky hair syndrome is an X-linked neurodegenerative disorder, causing tissue-specific increases in copper and metallothionein content [1].
• Spontaneous aortic aneurysms in blotchy mice [2].
• The Blo mouse is compared with other animal models of spontaneous and experimentally produced aneurysms [2].
• PURPOSE: Menkes and Wilson diseases are associated with retinal degeneration [3].
• An animal model of kinky hair syndrome is provided by mice mutant at the X-linked mottled locus [4].

Psychiatry related information on Atp7a

• Disturbed copper homeostasis occurs in patients with Menkes disease, an X-linked disorder characterized by mental retardation, neurodegeneration, connective tissue disorders, and early childhood death [5].
• Biochemical study on the critical period for treatment of the mottled brindled mouse [6].
• Hypothalamic self-stimulation and operant activity in the mottled mutant mouse [7].

High impact information on Atp7a

• Deletion of the promoter region in the Atp7a gene of the mottled dappled mouse [8].
• A murine model of Menkes disease reveals a physiological function of metallothionein [9].
• The LEC rat has a deletion in the copper transporting ATPase gene homologous to the Wilson disease gene [10].
• The murine homologue of the Menkes disease gene (MNK) was isolated from cDNA libraries, using human cDNA clones as probes, and by PCR [11].
• Tissues of the blotchy mouse contained two larger sizes of MNK mRNA demonstrating a likely defect in RNA splicing [11].

Chemical compound and disease context of Atp7a

• Propranolol prevents or delays the formation of aortic aneurysms in both the lathyritic turkey and the Blotchy mouse models [12].
• Intraperitoneal injections of cupric chloride prevent neuronal degeneration in the hemizygous brindled mottle mouse, MO br/Y, a murine model of kinky hair syndrome (KHS) in humans [13].
• Data from multicentre clinical trials have shown that 0.05% tretinoin emollient cream reduced fine wrinkling, surface roughness and mottled hyperpigmentation caused by photodamage [14].
• Sequence of a Menkes-type Cu-transporting ATPase from rat C6 glioma cells: comparison of the rat protein with other mammalian Cu-transporting ATPases [15].
• One Avy/a phenotype is identified by a mottled yellow coat and characterized by adult obesity, elevated circulating insulin levels, and impaired glucose tolerance [16].

Biological context of Atp7a

• In contrast, expression of an H1069Q mutant Wilson cDNA did not rescue the mottled phenotype, and immunofluorescence studies showed that this mutant Wilson protein was localized in the endoplasmic reticulum [17].
• Furthermore, expression of the Wilson cDNA rescued the mottled phenotype as evidenced by a reduction in copper accumulation and restoration of cell viability [17].
• Using RNA in situ hybridization we describe the distribution of mottled and toxic milk transcripts during mouse embryonic development [18].
• A 6 bp deletion of nucleotides 2478-2483, which can be predicted to affect the correct processing of the protein, was found in Atp7aMo-br and an A3189-->C nucleotide change, which results in lysine-->threonine amino acid substitution in the phosphorylation domain, was found in Atp7aMo-vbr [19].
• Based on these results, we conclude that a reduction in the ability of PAM to produce bioactive end-products involved in neuronal growth and development could contribute to many of the biological effects associated with Menkes disease [5].

Anatomical context of Atp7a

• Both Atp7a and Atp7b are expressed in glomeruli; however, Atp7b is also seen in the kidney medulla [20].
• That is, the brindled mutant and patients with classical Menkes disease are severely copper deficient and have profound neurological problems, while OHS patients and the blotchy mouse have a much milder phenotype with predominantly connective tissue defects [21].
• In this study, in an attempt to understand the basis for the brindled and blotchy phenotypes, the copper transport characteristics and intracellular distribution of the Mnk protein were assessed in cultured cells from these mutants [21].
• The mottled gene is expressed in all tissues throughout embryogenesis and is particularly strong in the choroid plexuses of the brain [18].
• Hepatic expression of both toxic milk and mottled is in the parenchyma, as opposed to blood cells [18].

Associations of Atp7a with chemical compounds

• Atp7a is required for these copper-dependent effects: Hippocampal neurons isolated from newborn Mo(br) mice reveal a marked sensitivity to endogenous glutamate-mediated NMDA receptor-dependent excitotoxicity in vitro, and mild hypoxic/ischemic insult to these mice in vivo results in significantly increased caspase 3 activation and neuronal injury [22].
• METHODS: Three groups of mice were studied: group I--normal littermates of blotchy mice; group II--untreated blotchy mice; group III--blotchy mice given either propranolol, atenolol, or nadolol [23].
• With exposure to either a strong (cadmium) or weaker (zinc) inducer of metallothionein, 64Cu accumulation was increased in normal cells, while there was no change from the already elevated level of 64Cu accumulation in blotchy cells.(ABSTRACT TRUNCATED AT 250 WORDS)[4]
• These data establish that a Menkes-type Cu-transporting ATPase is expressed in rat C6 and PC12 cells and strongly support the hypothesis that both neurons and glia are involved in maintaining Cu homeostasis in the central nervous system [24].
• Hydrocortisone treatment resulted in increased metallothionein synthesis in liver of mutant mice but had no ameliorative effect on the mottled-brindled disease [25].

Regulatory relationships of Atp7a

• A light microscopic study of interruptions of the internal elastic lamina (IIEL) showed that they developed in arteries of both Blotchy and control mice but to a greater extent in the Blotchy group where hypertension further increased their incidence [26].

Other interactions of Atp7a

• We have monitored the age-associated maintenance of two epigenetic systems--X inactivation and genomic imprinting--using the genes Atp7a and Igf2, respectively [27].
• The pathogenesis of aneurysm formation was studied in Blotchy (Blo) mice which have a hereditary defect in collagen and elastin cross-linking [2].
• To test the uniformity of cis-acting gene repression, 32 genetically identical F1 female mice were analyzed for differential expression of homologous alleles at three X-linked genes-Otc, Atp7a (= Mottled), and Hprt [28].
• Menkes protein (ATP7A) is a P-type ATPase involved in copper uptake and homeostasis [5].
• Menkes protein contributes to the function of peptidylglycine alpha-amidating monooxygenase [5].

Analytical, diagnostic and therapeutic context of Atp7a

• METHODS: RT/PCR was used to test for the presence of Wilson and Menkes mRNAs in mouse and human retinas and retinal pigment epithelial cell lines [3].
• Furthermore, no genomic deletions or alterations > 20 kb were detected in 10 independently derived Mo mutants using pulsed-field gel electrophoresis [29].
• We also describe the first Western blot data for Mnk in tissues, and these show normal levels of Mnk in mutant and brindled kidneys but none in liver [30].
• In the kidney, immunohistochemistry demonstrated Mnk in the proximal and distal tubules, the distribution is identical in mutant and normal [30].
• The susceptibility to aneurysm formation in the cerebral arteries of the circle of Willis was compared in female heterozygous 'Blotchy' and control mice subjected to unilateral carotid artery ligation either alone or associated with hypertension [26].

References