Trace element binding in the copper deficient mottled mutants in the mouse

Hunt, David M.; Port, Ann E.

doi:10.1016/0024-3205(79)90028-6

Cited by 29 publications

(9 citation statements)

References 22 publications

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“…Our experimental observa tions demonstrated that the copper contents of kidney and small intestine from the 7-dayold mutants were significantly greater than those in normal mice, and that liver, spleen, brain and serum copper contents in the mu tants and heterozygotes were low with the exception of serum and spleen in heterozy gotes. These results are similar to those ob served in brindled [Camakaris et al, 1979;Hunt and Port, 1979; and blotchy mice [Mann et al, 1981], In contrast to cop per, no significant differences in zinc levels in any tissue were evident.…”

Section: Discussionsupporting

confidence: 76%

“…It has been demonstrated that Menkes cells ac cumulate approximately 3-10 times more copper than normal cells [Goka et al, 1976;Horn, 1976;Chan et al, 1978; and that the excess copper accumu lated in the cytosol of the cells is bound to metallothionein (MT) [Beratis et al, 1978;Onishi et al, 1980;LaBadie et al, 1981aLaBadie et al, , 1981bBonewitz and Howell, 1981;Riordan and Jolicoeur-Paquet, 1982], Furthermore, it has been known that excessive amounts of copper in kidney or gut of the mottled mouse are sequestered by MT [Hunt and Port, 1979;Van den Hamer, 1980, 1981;Prohaska, 1983]. Various hypotheses have been proposed to explain the increased accumula tion of copper in the form of MT in cultured Menkes cells and mottled mice.…”

Section: Discussionmentioning

confidence: 99%

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Copper Metabolism in the Macular Mutant Mouse: An Animal Model of Menkes’s Kinky-Hair Disease

1988

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The tissue copper contents were measured in mutant (hemizygous macular male and homozygous macular female), heterozygous macular female and normal mice. The copper content in kidney and small intestine from 7-day-old mutant and heterozygote were extremely high compared to normal mice, whereas the copper content in other tissues (liver, brain, spleen and serum) was low. Copper content in whole body of mutant mice was extremely low at three stages (18 days gestation, 1 day old, and 7 days old) compared to normal mice with the exception of the mutant fetus at 14 days of gestation. Renal copper contents in the mutant fetus at 18 days of gestation and in the 1-day-old mutant were not changed compared to normal mice, whereas that in 7- and 14-day-old mutant mice was significantly elevated. Hepatic copper content of the mutant mice was extremely low at all stages compared to normal mice. Copper therapy was applied to 7-day-old mutant mice. At 1 day after injection, hepatic copper content in the mutants had increased slightly in comparison with the normal control mice, whereas renal copper content was extremely increased. At 7 days after injection, hepatic copper content in the mutants was decreased greatly in comparison with normal control mice, whereas an increase in renal copper content had remained.

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Section: Discussionsupporting

confidence: 76%

Section: Discussionmentioning

confidence: 99%

Copper Metabolism in the Macular Mutant Mouse: An Animal Model of Menkes’s Kinky-Hair Disease

1988

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“…At the broad range of metal concentrations tested herein, and absent extreme and possibly toxic concentrations of these metals, the accumulation data are congruent with those in a related study of kinky hair syndrome lymphoblasts (34). The conclusions are further supported by results of whole animal studies in blotchy (30,35) and brindled (22) mutants, and are consonant with inferences drawn from work on copper and zinc interrelationships in hepatocytes (1 3, 36) and from the finding of equivalent zinc contents in kinky hair syndrome and normal fibroblasts (2). Taken together with the larger body of data on the Menkes' and mottled mutations, it is reasonable to infer that the defect in both species affects specifically the function of a copper storage or transport system, with the metabolism of zinc and cadmium unaffected.…”

Section: Discussionsupporting

confidence: 53%

“…Studies in the mottled mouse have served to confirm and extend the phenotype of kinky hair syndrome (3,4,11,14,21,22,27,(30)(31)(32)(33)35). Our present studies in blotchy cultured skin fibroblasts were designed to ask whether the expression of the blotchy mutation causes abnormalities in the metabolism of trace metals other than copper at the cellular level, and to ascertain whether we can differentiate mutant and normal cells according to their response to metallothionein inducers.…”

Section: Discussionmentioning

confidence: 99%

Trace Metal Metabolism in Cultured Skin Fibroblasts of the Mottled Mouse: Response to Metallothionein Inducers

Packman

O'Toole

1984

Pediatr Res

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ABSTRACT. Menkes' kinky hair syndrome is a lethal Xlinked disorder marked by tissue-specific increases in copper content. An animal model of kinky hair syndrome is provided by mice mutant at the X-linked mottled locus. The basic defect is unknown. In order to discriminate among potential etiologies, we asked whether the expression of the mottled mutation causes abnormalities in the metabolism of trace metals other than copper in hemizygous mottled (blotchy) cultured skin fibroblasts, and whether we can differentiate mutant and normal cells according to their response to metal inducers of metallothionein. Blotchy fibroblasts accumulated up to 12 times more "Cu than control (littermate) cells, over time and over a range of 6 4 C~ concentrations. A saturable high affinity component to accumulation over a fixed time interval was revealed in these studies. While uptake kinetics were indistinguishable in mutant and control cells, the patterns of 64Cu exit differed. In both cell types, the rate of release of a rapidly exchangeable fraction of newly acquired 'j4Cu was similar. However, in mutant cells, a larger fraction of recently accumulated 6 4 C~ is retained. In contrast to the results for "CU, accumulation and exit of 65Zn and '09Cd were not distinguishable in mutants and controls. With exposure to either a strong (cadmium) or weaker (zinc) inducer of metallothionein, "CU accumulation was increased in normal cells, while there was no change from the already elevated level of 6 4 C~ accumulation in blotchy cells. In contrast, the effects of metal inducers of metallothionein on 65Zn or '09Cd accumulation in mutant cells were indistinguishable from the effects on controls. The present observations reveal that blotchy fibroblasts exhibit normal accumulation and exit of metals other than copper, and evince a differential response to metallothionein inducers, which response is also limited to the accumulation of copper. When considered together with the larger body of data on the kinky hair syndrome and mottled mutation, we infer that the defect in both species resides in the function of a thionein or other protein specifically binding copper; or in an altered transport system specifically affecting copper. (Pediatr Res 18:1282-1286, 1984

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“…30 We postulated that the higher metallothionein-I (Table), even in the face of slightly higher tissue copper contents in these young mutant kidneys.20 COMMENT The basic defect in Menkes' kinky-hair syndrome and in the murine analogue for that disease, the mottled mouse, is unknown. It was earlier thought that the phenotype in both species was attributable to defective gastrointestinal absorption of copper, relative copper deficiency, and consequent reduced activity of a number of cuproenzymes.12h'25 With the recognition that the defective gastrointestinal absorption was only one manifestation of a tissuespecific copper sequestration and distribution defect,Jh attention turned to mechanisms of intracel¬ lular copper binding and to the role of metallothio¬ neins in the generation of the disease manifestations in both species.…”

Section: Metabolism Of Copper Zinc and Cadmium In The Mo Mousementioning

confidence: 99%

Regulation of Copper Metabolism in the Mottled Mouse

Packman¹

1987

Arch Dermatol

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Menkes' kinky-hair syndrome is an X-linked recessive neurodegenerative and connective-tissue disorder, with decreased serum copper and ceruloplasmin-copper oxidase concentrations and tissue-specific increases in copper content. Clinical manifestations can be related to relative copper deficiency and reduced activity of cuproenzymes in multiple organs. An animal model is provided by mice hemizygous for mutant alleles, such as the blotchy allele, at the X-linked mottled locus. This locus may be homologous in mouse and man. The basic defect is unknown but has been thought to reside in the regulation of the function or synthesis of metallothioneins. In the blotchy mouse and in cultured skin fibroblasts derived therefrom, we showed that the mutation specifically affects the metabolism of copper and not other trace metals. Excessive accumulation and abnormal (reduced) exit kinetics were demonstrated for copper but not for the related trace metals cadmium and zinc. While metallothionein-I messenger RNA (mRNA) concentrations were elevated in blotchy fibroblasts, the elevations in metallothionein-I mRNA in response to metallothionein inducers (cadmium, copper) were similar in blotchy and control cells. Further, metallothionein-I mRNA levels were indistinguishable in mutant and control fibroblasts containing equivalent intracellular copper concentrations. Finally, metallothionein-I mRNA content was not elevated in blotchy kidneys at early developmental stages, before storage of excessive copper. The aggregate data suggest that the basic defect in the blotchy mouse--and, by analogy, in Menkes' syndrome--does not reside in defective modulation of metallothionein function and does not cause abnormal regulation of metallothionein synthesis.

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Trace element binding in the copper deficient mottled mutants in the mouse

Cited by 29 publications

References 22 publications

Copper Metabolism in the Macular Mutant Mouse: An Animal Model of Menkes’s Kinky-Hair Disease

Copper Metabolism in the Macular Mutant Mouse: An Animal Model of Menkes’s Kinky-Hair Disease

Trace Metal Metabolism in Cultured Skin Fibroblasts of the Mottled Mouse: Response to Metallothionein Inducers

Regulation of Copper Metabolism in the Mottled Mouse

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