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Mutation analysis provides additional proof that mottled is the mouse homologue of Menkes' disease
Abstract:
Menkes' disease (MD) and occipital horn syndrome (OHS) are allelic X-linked disorders caused by mutations in the copper ion transporting ATPase, ATP7A. Genetic, phenotypic and biochemical data suggest that mottled mutants in the mouse, which range in severity and phenotype, are caused by mutations in Atp7a, the mouse homologue of ATP7A. As the only causal mutation in Atp7a has been reported in one very mild allele thought to be a model for OHS, Atp7aMo-blo (mottled blotchy), we sequenced the entire 4.5 kb coding region of three other mottled mutants, two of which are thought to be models for classical MD (AtpaMo-br, AtpaMo-13H) and one with a slightly milder phenotype (Atp7aMo-vbr). Although no causal mutation was found in Atp7aMo-13H, mutations which can be predicted to affect Atp7a function were identified in Atp7aMo-br and Atp7aMo-vbr. A 6 bp deletion of nucleotides 2478-2483, which can be predicted to affect the correct processing of the protein, was found in Atp7aMo-br and an A3189-->C nucleotide change, which results in lysine-->threonine amino acid substitution in the phosphorylation domain, was found in Atp7aMo-vbr. Thus we provide further proof that mottled mutants will provide excellent models for MD as well as OHS.
Insights
Mottled mouse mutants provide valuable models for Menkes disease (MD) and occipital horn syndrome (OHS). Researchers identified specific ATP7A gene mutations in these mouse models, confirming their utility for studying these copper transport disorders.
Area of Science:
- Genetics
- Molecular Biology
- Biochemistry
Background:
- Menkes disease (MD) and occipital horn syndrome (OHS) are X-linked disorders resulting from ATP7A gene mutations affecting copper transport.
- Mottled mouse mutants exhibit variable phenotypes, suggesting they are models for MD and OHS, but causal mutations were largely uncharacterized.
Purpose of the Study:
- To identify mutations in the ATP7A gene in three distinct mottled mouse mutants.
- To confirm the utility of these mouse models for studying human copper transport disorders.
Main Methods:
- Sequencing of the entire coding region of the ATP7A gene in Atp7aMo-br, Atp7aMo-13H, and Atp7aMo-vbr mouse mutants.
- Analysis of identified mutations for their predicted impact on ATP7A protein function.
Main Results:
- No mutation was found in the Atp7aMo-13H mutant.
- A 6 bp deletion (nucleotides 2478-2483) affecting protein processing was identified in Atp7aMo-br.
- An A3189-->C nucleotide change causing a lysine to threonine substitution in the phosphorylation domain was found in Atp7aMo-vbr.
Conclusions:
- Specific ATP7A mutations were identified in mottled mouse mutants, validating them as models for Menkes disease and occipital horn syndrome.
- These findings provide further evidence for the genetic basis of these disorders and the utility of mouse models in research.