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,**,3
* Departments of Anesthesiology and Critical Care Medicine and Pediatrics, The Johns Hopkins University and School of Medicine and ** Department of International Health, The Johns Hopkins University School of Public Health, Baltimore, MD
3 To whom correspondence should be addressed. E-mail: zharris1{at}jhmi.edu.
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ABSTRACT |
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 TOP ABSTRACT LITERATURE CITED |
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KEY WORDS: • copper • ceruloplasmin • Wilson disease • Menkes disease • aceruloplasminemia
Copper (Cu) is an essential transition metal required for the activity of multiple mammalian enzymes (Table 1). Through its unique ability to exist in distinct redox states, copper is able to function as a critical catalyst. The diversity of function and tissue expression of these proteins reveal an important role for copper in mammalian systems. Ubiquitously expressed, copper, zinc-superoxide dismutase (Cu,Zn-SOD)
4 is an antioxidant required for the dismutation of superoxide radicals to hydrogen peroxide. Cu, Zn-SOD represents 1% of the total cell's proteins (1). Genetic defects in this enzyme are associated with amyotrophic lateral sclerosis (ALS) (2). Cytochrome c oxidase is necessary for mitochondrial respiration. Tyrosinase is required for melanin production. A lack of lysyl oxidase is manifested by a laxity in collagen and skin and reflects a defect in collagen and elastin crosslinking. The multicopper oxidases, ceruloplasmin and hephaestin, represent a family of copper-containing proteins that regulate the efficiency of iron transport. Dopamine ß-hydroxylase is important in catecholamine production. Peptidylglycine 
-amidating mono-oxygenase (PAM) is required for neuropeptide and peptide hormone processing.
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2 mg/d, from the diet (e.g., legumes, potatoes, grains, shellfish, beef) across the small intestine (3). The liver represents the predominant storage organ for copper. Excess copper that is absorbed is excreted in bile and eliminated in feces. A stored hepatic copper pool presumably regulated by metallothioneins and glutathione has been previously described (4). Free copper rarely exists in vivo for it can readily participate in oxygen radical formation via Fenton and Haber-Weiss chemistry. As such, copper has multiple specific intracellular copper chaperones to traffic it between cellular compartments. However, no specific chaperone has yet been identified that transports copper in serum. Presumably, copper bound to either albumin or histidine is trafficked through the bloodstream for delivery to tissues or storage in the liver (5). Copper is imported into the hepatocyte via the high-affinity human copper transporter, hCtr1 (6, 7). Initially identified by functional complementation studies in yeast, targeted disruption of the murine ctr1 gene through homologous recombination resulted in an embryonic lethal phenotype suggesting a critical role for mCtr1 in copper homeostasis and embryonic development (8, 9). Characterization of hCtr1 confirms localization on the plasma membrane consistent with its role as a copper transporter (10). In certain cell lines, intracellular vesicular perinuclear distribution of hCtr1 suggests that this copper transporter not only traffics copper into the cell but also participates in the intracellular compartmentalization of this transition metal (10). Once intracellular, copper has one of four different possible fates: i) joining the copper/metallothionein pool, ii) trafficking to the mitochondria for cytochrome c oxidase incorporation via the copper chaperone cox17 (11), iii) binding to CCS (copper chaperone for SOD) for delivery to nascent Cu, Zn-SOD (12), or iv) trafficking to the Wilson disease P-type ATPase, which resides in the trans-golgi network (TGN), by HAH1 (human atox-1 homologue) for subsequent copper incorporation into the cuproprotein ceruloplasmin (Fig. 1) (13). Localization studies of the Wilson disease P-type ATPase show redistribution of the ATPase from the TGN to a vesicular compartment that migrates out toward the biliary epithelium under conditions of high copper concentration (14). This provides a possible mechanism for copper excretion in bile.
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Wilson disease (autosomal recessive) and Menkes disease (X-linked) represent the most well recognized and understood disorders of copper homeostasis. The Wilson disease P-type ATPase and the Menkes P-type ATPase are functionally homologous and share 67% protein identity (17). These copper transport proteins differ in tissue and developmental expression only. The Wilson disease P-type ATPase resides predominantly on the TGN membrane within the hepatocyte and thus, mutations in the Wilson disease P-type ATPase clinically present as disorders of copper excess secondary to an inability to eliminate copper from the cell, either excreted in bile or secreted as holoceruloplasmin. Patients develop liver disease secondary to toxic levels of copper accumulation. Psychiatric and basal gangliar symptoms develop as a result of copper deposition in the brain after "copper leakage" from the liver. Kayser-Fleischer rings arise, similarly, from copper deposition in the cornea.
Menkes P-type ATPase is located on the TGN membrane of the placenta, gut and brain. Copper that crosses the TGN in these tissues is intended for delivery to supply a growing fetus, dietary requirements for the organism and the developing brain. Mutations in the Menkes P-type ATPase clinically appear as disorders of copper deficiency and are characterized by defects in essential copper enzymes: hypopigmented hair secondary to a tyrosinase deficiency, connective tissue abnormalities and aortic aneurysms secondary to defects in lysyl oxidase activity, kinky hair syndrome resulting from reduced keratin crosslinking and severe neurodegeneration, presumably a result of a lack of cytochrome c oxidase, dopamine ß-hydroxylase and PAM. Patients suffering from Menkes disease die within the first few years of life.
A number of animal models to study copper homeostasis have been identified and generated. The mottled mouse (18), the Atox-1–deficient mouse (19) and the mctr1 knockout mouse (9) reveal the importance of adequate copper intake during embryogenesis and early development. They provide valuable insight into the pathogenesis of Menkes disease. The mottled mouse represents the first of a family of Menkes mouse models to be identified (18). Random X-linked inactivation of tyrosinase results in a mottled coat color in female carriers. The clinical variability of the Menkes mouse models is secondary to variable tissue expression and varies from the classic Menkes (brindled mouse, macular mouse) and mild Menkes (viable brindled mouse, blotchy mouse). The Atox-1–deficient mouse is lacking the copper chaperone HAH1, essential for copper delivery to the Wilson disease/Menkes P-type ATPase. The phenotype of the Atox-1–deficient mouse is one of Menkes disease for there is an inability to traffic copper into the circulation across the placenta (19). As predicted, the placenta from Atox-1–deficient mice has an inappropriately high copper content in the face of fetal copper deficiency. Runted knockout mice die shortly after birth manifesting skin laxity, hypopigmentation and seizures. The mctr1 knockout mouse is embryonic lethal, revealing the essential nature of this copper transport protein in the delivery of copper to tissues (9).
Animal models of Wilson disease include the toxic milk mouse (20) and the Long-Evans Cinnamon (LEC) rat (21). Both rodent models develop hepatocellular damage from abnormal copper accumulation associated with mutations in the Wilson disease P-type ATPase but neither exhibit the neurologic symptoms associated with the human disease. The Bedlington terrier demonstrates an autosomal recessive copper toxicosis that resembles Wilson disease but lacks any mutation in the Wilson disease locus (22). Linkage disequilibrium mapping has revealed a mutation in the MURR1 gene that is involved in this canine copper toxicosis (22). The function of this gene remains unknown.
For many years serum ceruloplasmin was assumed to be the predominant copper transport protein given the vast majority of copper contained in this protein. This -2 glycoprotein synthesized and secreted by hepatocytes contains six atoms of copper (23). Three copper atoms in the protein core participate in the capture of electrons from oxygen whereas a trinuclear copper cluster (24) at the interface of the amino and carboxy termini is essential for ferroxidase activity, oxidizing Fe2+/ferrous to Fe3+/ferric iron (25,
26). The identification of a neurodegenerative disorder associated with a lack of holoceruloplasmin due to mutations in the ceruloplasmin gene, resulting in a disruption of iron homeostasis, not copper homeostasis, provided the first compelling evidence that ceruloplasmin did not have a role as a primary copper transporter. Patients with aceruloplasminemia, despite an absence of ceruloplasmin in their serum, have no evidence of copper deficiency or abnormalities in copper metabolism.
First described by Miyajima, patients with aceruloplasminemia present in adulthood with retinal degeneration, neurodegeneration and diabetes mellitus (27– 29). Families have been identified lacking serum ceruloplasmin and presenting with basal gangliar degeneration manifest as dysarthria, dystonia, ataxia, cogwheel rigidity and memory loss consistent with a Parkinson-like syndrome. Clinical screening, including T2-weighted MRI studies, revealed iron accumulation in the basal ganglia, pancreas, liver and retina. Molecular genetic analysis of these families has revealed the presence of inherited mutations within the ceruloplasmin gene (30– 35). The presence of these mutations in conjunction with the clinical and pathological findings demonstrates an essential role for ceruloplasmin in iron metabolism.
Laboratory analysis reveals absent serum ceruloplasmin, mild anemia, low serum iron, low transferrin saturation and an elevated ferritin. Examination of liver tissue biopsy specimens is remarkable for normal hepatic architecture without evidence of fibrosis or cirrhosis. Perls stain (36), which selectively stains Fe3+ iron, iron salts and hemosiderin a deep blue, confirms pathologic iron deposition in the liver. Copper stains are negative for excessive copper accumulation. T2-weighted MRI studies are specific for iron deposition in the basal ganglia and not copper. Autopsy studies have further shown pigmentary discoloration and cavitary degeneration of the basal ganglia and substantia nigra corresponding to increased iron deposition in these regions. Iron deposition in the retina corresponds with degeneration of rods and cones in the affected area. Further, selective iron deposition in the ß-islets of Langerhans of the pancreas is responsible for the diabetes mellitus observed in aceruloplasminemic patients.
To best examine the role of ceruloplasmin in iron metabolism, an approach requiring development of a transgenic murine model lacking ceruloplasmin was undertaken (37). The availability of this animal model would facilitate elucidation of the molecular mechanisms of cellular iron metabolism, in particular central nervous system iron trafficking. Additionally, utilizing this model would allow delineation of the in vivo characteristics of iron metabolism in aceruloplasminemia and help define the kinetics and cell specificity of iron accumulation in the brain. A region of the ceruloplasmin gene corresponding to a known mutation characterized previously in a family with aceruloplasminemia was deleted (31). Northern blot analysis reveals absent Cp mRNA in the knockout mice. Western blot analysis reveals normal serum ceruloplasmin levels in wild-type mice (Cp+/+), half-normal serum ceruloplasmin levels in heterozygote mice (Cp+/-) and no detectable serum ceruloplasmin in the homozygous mutant mice (Cp-/-). Additionally, aceruloplasminemic mice have no detectable serum ferroxidase activity confirming total absence of circulating serum ceruloplasmin. The aceruloplasminemic mouse accumulates iron predominantly in organs of the reticuloendolthelial system (37). These animals never develop diabetes mellitus or a progressive neurodegeneration similar to humans with the disease. Hematologic and serum iron indices are abnormal by 10 wk of age, with profound splenic and liver iron overload manifest by 8 mo of age. These findings suggest that ceruloplasmin play an essential role in regulating the efficiency of systemic iron efflux.
To determine the role of ceruloplasmin in copper homeostasis, copper metabolism was studied in the aceruloplasminemic mice. Ten-wk-old wild-type and aceruloplasminemic mice were both gavage fed and injected with radioactive 64Cu and serum 64Cu levels and 64Cu cpm/g tissue were determined (Fig. 2). No differences were found in copper absorption, distribution and clearance between Cp+/+ and Cp-/- mice with the exception of the presence of 64Cu-ceruloplasmin in the serum of Cp+/+ 3 h after the administration of the radiocopper. No differences in total copper content (as determined by atomic absorption spectroscopy) or 64Cu distribution (64Cu cpm/g tissue) were appreciated between kidney, heart, muscle, spleen or brain consistent with the observation that ceruloplasmin deficiency has no effect on copper metabolism (Table 2) (37). Atomic absorption spectroscopy reveals twice the levels of hepatic copper in the Cp-/- mice as compared to wild-type littermates. This increased copper accumulation was not associated with any histologic abnormalities. Hepatic architecture remained normal in the Cp-/- mice despite the increased copper content. A difference in hepatic copper content would occur if more copper were absorbed by the Cp-/- mouse or if less copper were excreted in the bile by the Cp-/- mouse as compared to the Cp+/+ mouse. No differences were appreciated in 64Cu absorption or in gallbladder 64Cu both 3 and 24 h after radiocopper gavage.
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FOOTNOTES |
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2 This work was supported by the National Institutes of Health (grants DK02464 and DK58086 to ZHL).
4 Abbreviations used: Cp, ceruloplasmin; Cu, Zn-SOD, copper, zinc-superoxide dismutase; hCtr, human copper transporter; PAM, peptidylglycine -amidating mono-oxygenase; TGN, trans-golgi network.
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LITERATURE CITED |
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