Primary biochemical defect in copper metabolism in mice with a recessive X-linked mutation analogous to Menkes' disease in man

Prins, Hans W.; Hamer, C.J.A. van den

doi:10.1016/s0162-0134(00)81002-8

Cited by 34 publications

(10 citation statements)

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“…Metallothioneins have been identified as the major intracellular metal-binding protein in a variety of normal (23) and mutant (2,5,6,24,25,32,34) tissues. An excessive accumulation of cadmium in kinky hair syndrome fibroblasts was invoked to support the postulate of a mutant metallothionein in this disorder (6), and additional work in those cells (6) suggested the existence of structurally abnormal metallothioneins with decreased affinity for copper.…”

Section: Discussionmentioning

confidence: 99%

“…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%

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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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Section: Discussionmentioning

confidence: 99%

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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“…Mo br mice serve as an animal model for Menkes disease and demonstrate similar neurological abnormalities (Fraser et al, 1953;Hunt, 1974;Prins and Van den Hamer, 1979;Lyon and Searle, 1990). Menkes disease is an X-linked recessive disorder that causes severe mental retardation, neurodegeneration, autonomic dysfunction, and death in affected males at 3-4 years of age (Menkes et al, 1962;Harris and Gitlin, 1996;Mercer, 1998).…”

Section: Momentioning

confidence: 94%

Pituitary Adenylyl Cyclase-Activating Peptides and α-Amidation in Olfactory Neurogenesis and Neuronal SurvivalIn Vitro

Hansel¹,

May

Eipper

et al. 2001

J. Neurosci.

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We investigated the role of amidated neuropeptides, and specifically pituitary adenylyl cyclase-activating polypeptide (PACAP), in olfactory neurogenesis and olfactory receptor neuronal survival. Using both immunohistochemistry and in situ hybridization, we find that both peptidylglycine ␣-amidating monooxygenase (PAM), the enzyme responsible for amidation and therefore activation of all amidated neuropeptides, and amidated PACAP are expressed in developing and adult olfactory epithelium. Amidated PACAP is highly expressed in proliferative basal cells and in immature olfactory neurons. The PACAP-specific receptor PAC 1 receptor is also expressed in this population, establishing that these cells can be PACAP responsive. Experiments were conducted to determine whether amidated neuropeptides, such as PACAP38, might function in olfactory neurogenesis and neuronal survival. Addition of PACAP38 to olfactory cultures increased the number of neurons to Ͼ250% of control and stimulated neuronal proliferation and survival. In primary olfactory cultures, pharmacologically decreased PAM activity, as well as neutralization of PACAP38, caused neuron-specific loss that was reversed by PACAP38. Mottled (Brindled) mice, which lack a functional ATP7A copper transporter and serve as a model for Menkes disease, provided an in vivo partial loss-of-function PAM knock-out. These mice had decreased amidated PACAP production and concomitant decreased numbers of olfactory receptor neurons. These data establish amidated peptides and specifically PACAP as having important roles in proliferation in the olfactory system and suggest that a similar function exists in vivo.

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“…Consequently, there is an abnormal copper distribution in various tissues, with increased copper accumulation in some organs (e.g. kid ney and intestinal mucosa), but decreased copper accu mulation in the brain [1,2], A mutation which arises spontaneously in the C57BL inbred mouse strain has provided an animal model of this clinical disorder [3][4][5]. The brindled mottled (Mobr) mutant mouse, referred to as the brindled mouse, can either be a hemizygous male or heterozygous female.…”

Section: Introductionmentioning

confidence: 99%

The Female Brindled Mouse as a Model of Menkes' Disease: The Relationship of Fur Pattern to Behavioral and Neurochemical Abnormalities

Martin¹,

Irino²,

Suzuki³

et al. 1991

Dev Neurosci

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The brindled mottled mutant mouse, a model of Menkes'' disease, has alterations in copper homeostasis which cause, among other sequelae, neuronal degeneration in selected areas of brain. This work examined the neurochemical changes at postnatal days (PND) 15, 30 and 60 in females heterozygous for the sex-linked brindled mutation. These data were compared to behavioral alterations and to fur coat color at these same time points. The brindled heterozygotic females had lower concentrations of norepinephrine (NE) in the cingulate cortex, and higher levels of dopamine or dopamine metabolites in the cingulate cortex, thalamus and hypothalamus across all ages, although the difference was greatest at PND 15. The brindled females were much less active than their normal littermates at PND 15, but the differences were no longer evident at PND 30 and 60. Mottling of the fur is believed to result from low tyrosinase activity caused by abnormalities in copper metabolism. The fur pattern and behavior of the brindled mice were highly correlated with NE levels in the cingulate cortex and thalamus. These data show that female brindled mice have neurochemical abnormalities similar to (if less severe than) the male hemizygotes, that these abnormalities are regionally specific, are most apparent prior to 30 days of age, and are linked to behavioral deficits. These data also show that the extent of such deficits can be predicted by a quantitative analysis of the fur pattern of these females.

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Primary biochemical defect in copper metabolism in mice with a recessive X-linked mutation analogous to Menkes' disease in man

Cited by 34 publications

References 2 publications

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

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

Pituitary Adenylyl Cyclase-Activating Peptides and α-Amidation in Olfactory Neurogenesis and Neuronal SurvivalIn Vitro

The Female Brindled Mouse as a Model of Menkes' Disease: The Relationship of Fur Pattern to Behavioral and Neurochemical Abnormalities

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