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.

Identification and analysis of 21 novel disease-causing amino acid substitutions in the conserved part of ATP7A

“…Together with nine mutations reported earlier [Das et al, 1994;Tümer et al, 1997;Levinson et al, 1997;Kaler 1998;Ambrosini and Mercer, 1999;Ogawa et al, 1999;Gu et al, 2001;Hahn et al, 2001] and four mutations in the murine homologue, atp7a [Cecchi et al, 1997;Levinson et al, 1997;Mori and Nishimura, 1997;Murata et al, 1997;Ohta et al, 1997;Reed and Boyd, 1997], a total number of 34 missense mutations are known to date in the part of ATP7A/ atp7a sequence encoding residues p.V842-p.S1404. The total number of substituted residues in this region is 30 (Table 1).…”

Menkes disease

“…Atp7a mutations of both mottled alleles have been identified. [47][48][49][50] When Mo br is treated with copper injections within the first week of postnatal period the mice survive and do not develop neurological symptoms. 51 Furthermore, transgenic expression of human ATP7A in Mo br could correct the phenotype even though copper defect was not completely corrected.…”

The Developmentally Regulated Expression of Menkes Protein ATP7A Suggests a Role in Axon Extension and Synaptogenesis

“…; Genbank sequence Q64430) [Grimes et al, 1997;Reed and Boyd, 1997], producing a functionally defi cient ATP7A protein. In fi broblasts, the mutant protein is unable to transport copper or to translocate in response to increased copper levels [La Fontaine et al, 1999].…”