PYCNODYSOSTOSIS, A LYSOSOMAL DISEASE CAUSED BY CATHEPSIN-K DEFICIENCY

Pycnodysostosis, an autosomal recessive osteochondrodysplasia characte rized by osteosclerosis and short stature, maps to chromosome 1q21. Ca thepsin K, a cysteine protease gene that is highly expressed in osteoc lasts, localized to the pycnodysostosis region. Nonsense, missense, an d stop codon mutations in the gene encoding cathepsin K were identifie d in patients. Transient expression of complementary DNA containing th e stop codon mutation resulted in messenger RNA but no immunologically detectable protein. Thus, pycnodysostosis results from gene defects i n a lysosomal protease with highest expression in osteoclasts. These f indings suggest that cathepsin K is a major protease in bone resorptio n, providing a possible rationale for the treatment of disorders such as osteoporosis and certain forms of arthritis.