Related Experiment Videos
Regulation of copper metabolism in the mottled mouse
1Department of Pediatrics, University of California, San Francisco 94143.
Abstract:
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.
Insights
Menkes' kinky-hair syndrome involves copper metabolism defects. Studies in blotchy mice show the mutation affects copper processing, not metallothionein regulation, suggesting a different underlying cause for this neurodegenerative disorder.
Area of Science:
- Genetics and Molecular Biology
- Biochemistry
- Neuroscience
Background:
- Menkes' kinky-hair syndrome is an X-linked neurodegenerative disorder.
- It is characterized by copper deficiency and impaired cuproenzyme activity.
- The underlying genetic defect remains unknown.
Purpose of the Study:
- To investigate the molecular basis of copper metabolism defects in Menkes' syndrome using the blotchy mouse model.
- To determine if the defect involves metallothionein synthesis or function.
Main Methods:
- Analysis of copper and trace metal metabolism in blotchy mouse fibroblasts.
- Measurement of metallothionein-I messenger RNA (mRNA) levels.
- Assessment of metallothionein-I mRNA induction by inducers like cadmium and copper.
Main Results:
- Blotchy mouse mutation specifically affects copper metabolism, not other trace metals.
- Excessive copper accumulation and abnormal exit kinetics were observed.
- Metallothionein-I mRNA levels were elevated but responded normally to inducers, and were not elevated in early-stage mutant kidneys.
Conclusions:
- The defect in blotchy mice, and by analogy Menkes' syndrome, does not stem from impaired metallothionein function or regulation.
- The findings suggest a novel mechanism underlying copper dysregulation in these conditions.