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The mottled mouse as a model for human Menkes disease: identification of mutations in the Atp7a gene
1Unité de Génétique Moléculaire Murine, Institut Pasteur, Paris, France.
Abstract:
Mutations in the Atp7a gene, the mouse homologue of the MNK (ATP7A) gene, have been suggested to be responsible for the mottled phenotype. To date, despite considerable effort, changes associated with the mottled mutations have been detected in only two such mutants. In this study, we identify changes in the level of Atp7a transcript and mutations which could explain the mottled phenotype in nine out of the 10 mutants analysed. The fluorescence-assisted mismatch analysis method used here has proved particularly well suited for mRNA scanning of heterozygous carrier animals, because of its ability to detect mutations even in the presence of an excess of wild-type mRNA. The three new underlying mutations identified at the Atp7a locus include a splice mutation and two missense mutations. While the spectrum of mutations detected in the Atp7a murine gene provides an explanation for at least part of the wide phenotypic variation observed in mottled mutant mice, there is a singular absence of deletions which are associated with a sizeable fraction of human Menkes syndrome cases.
Insights
Researchers identified mutations in the Atp7a gene, explaining the mottled phenotype in most analyzed mouse mutants. This study advances understanding of genetic variations linked to the mottled mouse phenotype.
Area of Science:
- Genetics
- Molecular Biology
- Developmental Biology
Background:
- Mutations in the Atp7a gene are implicated in the mottled mouse phenotype.
- Previous efforts detected Atp7a gene changes in only two mottled mutants.
Purpose of the Study:
- To identify genetic mutations in the Atp7a gene responsible for the mottled phenotype in mice.
- To investigate the spectrum of mutations within the Atp7a gene and their correlation with phenotypic variation.
Main Methods:
- Utilized fluorescence-assisted mismatch analysis (FAMA) for efficient mRNA scanning in heterozygous carrier mice.
- Analyzed Atp7a gene transcripts and DNA sequences in ten distinct mottled mouse mutants.
Main Results:
- Identified Atp7a gene mutations in nine out of ten analyzed mottled mouse mutants.
- Discovered three novel mutations at the Atp7a locus: one splice mutation and two missense mutations.
- FAMA proved effective in detecting mutations even with excess wild-type mRNA.
Conclusions:
- The identified Atp7a gene mutations explain a significant portion of the mottled phenotype and its variation in mice.
- The spectrum of mutations differs from human Menkes syndrome, notably lacking deletions.
- Further research into Atp7a gene function and mutation types is warranted.