ANALYSIS OF MNK, THE MURINE HOMOLOG OF THE LOCUS FOR MENKES-DISEASE, IN NORMAL AND MOTTLED (MO) MICE

Menkes disease (MNK) lies immediately proximal to phosphoglycerate kin ase (PGK1) in Xq13 in human. Phenotypic similarities between MNK patie nts 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 h ave been used to position the murine homologue of Menkes disease (MNK, Mnk) immediately proximal to, and within 150-200 kb of, phosphoglycer ate kinase (Pgk1) on the mouse X chromosome using interspecific backcr oss analysis and pulsed-field gel electrophoresis. A related autosomal locus has been mapped to mouse chromosome 18. RFLVs at Mnk between in bred 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 alterati ons to restriction fragments containing exons of the Mnk locus in 9 Mo mutants. Furthermore, no genomic deletions or alterations > 20 kb wer e detected in 10 independently derived Mo mutants using pulsed-field g el electrophoresis. As no deletions or alterations at the Mnk gene wer e found, we suggest that any mutations in Mnk that cause the Mo phenot ype are likely to be due to small changes at the nucleotide level and/ or small deletions (<20 kb) that lie outside the coding sequence. (C) 1994 Academic Press, Inc.