Analysis of Mnk, the murine homologue of the locus for Menkes disease, in normal and mottled (Mo) mice.

Menkes disease (MNK) lies immediately proximal to pphosphoglycerate kinase (PGK1) in Xq13 in human. Phenotypic similarities between MNK patients and murine mottled (Mo) mutants strongly suggest that both defects are caused by mutations at the same locus. Human MNK cDNA clones and a genomic subclone derived from a 40-kb YAC clone that includes Pgk1 have been used to position the murine homologue of Menkes disease (MNK, Mnk) immediately proximal to, and within 150-200 kb of, phosphoglycerate kinase (Pgk1) on the mouse X chromosome using interspecific backcross analysis and pulsed-field gel electrophoresis. A related autosomal locus has been mapped to mouse chromosome 18. RFLVs at Mnk between inbred strains of mice that show a strong association with the presence of the Mo phenotype have been detected. Hybridization of 4.1 kb of the 4.5-kb MNK coding sequence failed to reveal any deletions or alterations to restriction fragments containing exons of the Mnk locus in 9 Mo mutants. Furthermore, no genomic deletions or alterations > 20 kb were detected in 10 independently derived Mo mutants using pulsed-field gel electrophoresis. As no deletions or alterations at the Mnk gene were found, we suggest that any mutations in Mnk that cause the Mo phenotype are likely to be due to small changes at the nucleotide level and/or small deletions (< 20 kb) that lie outside the coding sequence.