STRUCTURE AND CHROMOSOMAL ASSIGNMENT OF THE HUMAN CATHEPSIN-K GENE

Cathepsin K is a recently identified lysosomal cysteine proteinase tha t is the major protease responsible for bone resorption and remodeling . Mutations in this gene cause the sclerosing osteochondrodysplasia py cnodysostosis. To assess its evolutionary relatedness to other cystein e proteases and to facilitate mutation identification in patients with pycnodysostosis, a genomic clone, 74e16, containing the cathepsin K g ene was isolated from a human PAC library, and the cathepsin K genomic structure was determined. The cathepsin K gene contained eight exons and spanned approximately 9 kb. The transcription initiation site, det ermined by primer extension analysis, was 169 nucleotides upstream fro m the translation initiation site. The 5'-flanking region lacked a TAT A box but contained two AP1 sites. Comparison of genomic and cDNA sequ ences suggested that this flanking sequence may be the major promoter in osteoclasts and macrophages. Cathepsin K was mapped to chromosome 1 q21 by fluorescence in situ hybridization and found to reside within 1 50 kb of an evolutionarily related cysteine protease, cathepsin S. The se findings expand our understanding of the papain family lysosomal cy steine proteases and should facilitate mutation analysis in pycnodysos tosis. (C) 1997 Academic Press.