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Isolation of a candidate gene for Menkes disease and evidence that it encodes a copper-transporting ATPase
C Vulpe1, B Levinson, S Whitney
1Department of Biochemistry, Howard Hughes Medical Institute, San Francisco, California.
Abstract:
Menkes disease is an X-linked disorder of copper transport characterized by progressive neurological degeneration and death in early childhood. We have isolated a candidate gene (Mc1) for Menkes disease and find qualitative or quantitative abnormalities in the mRNA in sixteen of twenty-one Menkes patients. Four patients lacking Mc1RNA showed rearrangements of the Menkes gene. The gene codes for a 1,500 amino acid protein, predicted to be a P-type cation-transporting ATPase. The gene product is most similar to a bacterial copper-transporting ATPase and additionally contains six putative metal-binding motifs at the N-terminus. The gene is transcribed in all cell types tested except liver, consistent with the expression of the Menkes defect.
Insights
Researchers identified a candidate gene (Mc1) for Menkes disease, an X-linked copper transport disorder. Abnormalities in this gene were found in most patients, implicating it in the disease pathology.
Area of Science:
- Genetics
- Molecular Biology
- Biochemistry
Background:
- Menkes disease is a severe X-linked genetic disorder affecting copper transport.
- It leads to progressive neurological degeneration and is typically fatal in early childhood.
Purpose of the Study:
- To identify and characterize the gene responsible for Menkes disease.
- To investigate the genetic basis of copper transport defects in affected patients.
Main Methods:
- Isolation of a candidate gene (Mc1) for Menkes disease.
- Analysis of mRNA from Menkes patients to detect gene abnormalities.
- Investigation of gene rearrangements in patients lacking Mc1RNA.
Main Results:
- Qualitative or quantitative mRNA abnormalities in the Mc1 gene were identified in 16 out of 21 Menkes patients.
- Four patients exhibited gene rearrangements in the absence of detectable Mc1RNA.
- The identified gene encodes a 1,500 amino acid protein, a putative P-type cation-transporting ATPase with metal-binding motifs.
Conclusions:
- The Mc1 gene is a strong candidate for Menkes disease.
- Mutations in the Mc1 gene are a significant cause of Menkes disease, affecting copper transport.
- The gene's expression pattern, absent in the liver, aligns with the known Menkes defect.