Animal Models of Menkes Disease

Mercer, Julian F. B.; Ambrosini, Loreta; Horton, S.; Gazeas, Sophie; Grimes, Andrew

doi:10.1007/978-1-4615-4859-1_8

Cited by 19 publications

(8 citation statements)

References 33 publications

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“…6 A mouse model called the mottled mouse has also been shown to have mutations in the mouse homolog of ATP7A with different mutations causing a variety of neurologic manifestations and degeneration of neurons. 10 Copper deficiency induced in rats by the copper chelater iminodiproprionitrile causes aberrant behavior, including abnormal movements and gait difficulties, and also causes vacuolization of the ventral horn. 4 Lastly, mutations in copper/zinc superoxide dismutase cause familial ALS and, although the exact mechanism of this disease is not known, improper metal binding has been proposed as a mechanism by which mutations cause their toxic gain of function.…”

Section: Discussionmentioning

confidence: 99%

Motor neuron disease associated with copper deficiency

Weihl

Lopate

2006

Muscle and Nerve

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Copper deficiency in humans is a rare cause of myeloneuropathy that usually presents with a spastic ataxic gait, hyperreflexia, and distal sensory loss similar to that seen in patients with subacute combined degeneration. We describe three copper-deficient patients, two of whom were referred with a presumptive diagnosis of amyotrophic lateral sclerosis, who had progressive asymmetric weakness or electrodiagnostic findings of proximal and distal denervation suggestive of lower motor neuron disease. Copper replacement resulted in stabilization or mild improvement in weakness. The clinical spectrum of human copper deficiency should include lower motor neuron disease in addition to a syndrome of spastic ataxia.

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Section: Discussionmentioning

confidence: 99%

Motor neuron disease associated with copper deficiency

Weihl

Lopate

2006

Muscle and Nerve

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“…We investigated two independently derived genetic models of copper overload containing mutations in the same gene to discriminate between cell-specific effects and the effects of copper. Both of these mutations result in severe loss of function in the Atp7a gene (33). Both mutants result in a cellular defect in copper efflux that leads to similar levels of intracellular copper accumulation in cultured cells.…”

Section: Discussionmentioning

confidence: 99%

“…Excess copper is normally exported by the ATP7A copper transporting P-type ATPase, which translocates from the trans-Golgi network (TGN) to the plasma membrane in the presence of elevated copper (45). Mutations in ATP7A in both humans (Menkes disease) and mice (mottled mouse) lead to reduced intestinal basolateral export of copper and subsequent systemic copper deficiency (33). All cultured cells tested, with the exception of hepatic cells, from mottled mice accumulate copper to abnormally high levels in normal culture media (12,32).…”

mentioning

confidence: 99%

Gene expression profiling in chronic copper overload reveals upregulation ofPrnpandApp

Armendariz

González

Loguinov

et al. 2004

Physiological Genomics

102

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The level at which copper becomes toxic is not clear. Several studies have indicated that copper causes oxidative stress; however, most have tested very high levels of copper exposure. We currently have only a limited understanding of the protective systems that operate in cells chronically exposed to copper. Additionally, the limits of homeostatic regulation are not known, making it difficult to define the milder effects of copper excess. Furthermore, a robust assay to facilitate the diagnosis of copper excess and to distinguish mild, moderate, and severe copper overload is needed. To address these issues, we have investigated the effects on steady-state gene expression of chronic copper overload in a cell culture model system using cDNA microarrays. For this study we utilized cells from genetic models of copper overload: fibroblast cells from two mouse mutants, C57BL/6- Atp7aMobr and C57BL/6- Atp7aModap. These cell lines accumulate copper to abnormally high levels in normal culture media due to a defect in copper export from the cell. We identified 12 differentially expressed genes in common using our outlier identification methods. Surprisingly, our results show no evidence of oxidative stress in the copper-loaded cells. In addition, candidate components perhaps responsible for a copper-specific homeostatic response are identified. The genes that encode for the prion protein and the amyloid-β precursor protein, two known copper-binding proteins, are upregulated in both cell lines.

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“…The high affinity copper uptake protein Ctr1 is responsible for making copper that enters via the apical membrane available in the cytosol for further utilization (1), whereas the copper-transporting ATPase ATP7A facilitates copper exit from the enterocytes into circulation (2) (Figure 1). Complete genetic inactivation of either transporter in experimental animals is embryonically lethal (3)(4)(5). However, partial inactivation or tissue specific inactivation of ATP7A or Ctr1, respectively, in either case is associated with copper accumulation in the intestine, impaired copper entry into the bloodstream, and severe copper deficiency in many organs and tissues (1).…”

Section: Copper Homeostasis In Mammalsmentioning

confidence: 99%