Intragenic deletions at Atp7a in mouse models for Menkes disease.

Mottled mice have mutations in the copper-transporting ATPase Atp7a. They are proven models for the human disorder Menkes disease (MD), which results from mutations in a homologous gene. Mottled mice can be divided into three classes: class 1, in which affected males die before birth; class 2, in which affected males die in the early postnatal period; and class 3, in which affected males survive to adulthood. In humans, it has been shown that mutations that lead to a complete absence of functional protein cause classical MD, which is characterized by death of boys in early childhood. We hypothesized that the most severely affected mottled alleles would be the most likely to carry mutations equivalent to those causing classical MD and therefore undertook mutational analysis of several class 1 mottled alleles to assess whether these were appropriate models for the disease at the molecular level. Two novel mutations, a deletion of exons 11-14 in mottled spot and an insertion in exon 10 leading to missplicing in mottled candy, were identified. However, these are both "in-frame" mutations, as are the other eight Atp7a mutations reported to date, and therefore no frameshift or nonsense mutations have yet been associated with the mottled phenotype. This contrasts with the mutation spectrum associated with MD, emphasizing the need for caution when mottled mice are used as models for the clinical disorder.