Identification of three novel mutations in the MNK gene in three unrelatedJapanese patients with classical Menkes disease

Menkes disease is an X-linked recessive disorder of the copper membrane tra nsport system caused by mutations to the Menkes (MNK) gene. We identified t hree novel mutations of the MNK gene in three unrelated Japanese patients w ith classical Menkes disease by analyzing reverse-transcriptase polymerase chain reaction products and genomic DNA of the MNK gene. Firstly, an insert ional mutation was found, 1173 ins A, which led to a premature termination and resulted in a very immature Menkes protein. Secondly, we found a point mutation, T2763G, resulting in a leucine-to-arginine conversion, which we p redicted would cause a change in the secondary structure of the Menkes prot ein. Finally, we identified a splicing mutation, 2317+5G>C, which resulted in the skipping of both exons 8 and 9 or exon 9 only, and led to a truncati on of the protein. Each of these mutations is hypothesized to destroy coppe r-ATPase-mediated copper transport. We propose that each of these mutations in the MNK gene plays a causative role in the disease.