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Molecular genetics and pathophysiology of Menkes disease
1Department of Pediatrics, Teikyo University School of Medicine, Tokyo, Japan. hkodama@med.teikyo-u.ac.jp
Abstract:
The molecular genetics and pathophysiology of Menkes disease and an animal model for this disease are reviewed. The Menkes gene, located on chromosome X13.3, encodes a copper-transporting ATPase, as shown by the sequencing of a cDNA of 4500 bp. Mutations in the Menkes gene in patients with Menkes disease show great variety, including missense, nonsense, deletion and insertion mutations. Mutations in the Menkes gene have also been identified in patients with mild Menkes disease or occipital horn syndrome, showing that these diseases are allelic variants of Menkes disease. Mutations in the mottled gene, the murine homolog of the Menkes gene, have been demonstrated in mottled mutant mice that display biochemical and phenotypic abnormalities similar to those observed in patients with Menkes disease. In affected cells, copper significantly accumulates as metallothionein-bound copper in the cytosol and copper transport to the organelles, as well as copper efflux, is disturbed. As a result, cuproenzymes cannot receive the copper necessary for their normal function. Thus, the objective in treatment of Menkes disease and occipital horn syndrome is to deliver copper to the intracellular compartments where cuproenzymes are synthesized.
Insights
Menkes disease results from mutations in the copper-transporting ATPase gene, disrupting cellular copper transport. Treatment aims to deliver copper to cuproenzymes for proper function.
Area of Science:
- Molecular Genetics
- Pathophysiology
- Biochemistry
Background:
- Menkes disease is a rare genetic disorder affecting copper transport.
- The Menkes gene (MNK) encodes a copper-transporting ATPase.
- Mutations in MNK lead to cellular copper deficiency and related pathologies.
Purpose of the Study:
- To review the molecular genetics and pathophysiology of Menkes disease.
- To discuss the role of the Menkes gene and its mutations.
- To explore an animal model for Menkes disease.
Main Methods:
- Review of existing literature on Menkes disease genetics and pathophysiology.
- Analysis of Menkes gene sequencing data.
- Examination of studies on the mottled mouse model.
Main Results:
- The Menkes gene, located on chromosome X13.3, encodes a copper-transporting ATPase.
- Diverse mutations (missense, nonsense, deletion, insertion) in the Menkes gene cause Menkes disease and allelic variants like occipital horn syndrome.
- The murine mottled gene is homologous to the Menkes gene, and mutations cause similar abnormalities in mice.
- Affected cells exhibit copper accumulation in the cytosol and impaired copper transport to organelles.
- Cuproenzymes are deprived of essential copper, leading to dysfunction.
Conclusions:
- Menkes disease and occipital horn syndrome are allelic variants caused by Menkes gene mutations.
- The mottled mouse model accurately reflects Menkes disease pathophysiology.
- Therapeutic strategies should focus on delivering copper to intracellular compartments for cuproenzyme synthesis.