MUTATION ANALYSIS PROVIDES ADDITIONAL PROOF THAT MOTTLED IS THE MOUSEHOMOLOG OF MENKES DISEASE

Menkes' disease (MD) and occipital horn syndrome (OHS) are allelic X-l inked disorders caused by mutations in the copper ion transporting ATP ase, ATP7A, Genetic, phenotypic and biochemical data suggest that mott led mutants in the mouse, which range in severity and phenotype, are c aused by mutations in Atp7a, the mouse homologue of ATP7A, As the only causal mutation in Atp7a has been reported in one very mild allele th ought to be a model for OHS, Atp7a(Mo-blo) (mottled blotchy), we seque nced the entire 4.5 kb coding region of three other mottled mutants, t wo of which are thought to be models for classical MD (Atpa(Mo-br), At pa(Mo-13H)) and one with a slightly milder phenotype (Atp7a(Mo-vbr). A lthough no causal mutation was found in Atp7a(Mo-13H), mutations which can be predicted to affect Atp7a function were identified in Atp7a(Mo -br) and Atp7a(Mo-vbr). A 6 bp deletion of nucleotides 2478-2483, whic h can be predicted to affect the correct processing of the protein, wa s found in Atp7a(Mo-br) and an A(3189)-->C nucleotide change, which re sults in lysine-->threonine amino acid substitution in the phosphoryla tion domain, was found in Atp7a(Mo-vbr), Thus we provide further proof that mottled mutants will provide excellent models for MD as well as OHS.