Clinical and animal research findings in pycnodysostosis and gene mutations of cathepsin K from 1996 to 2011

Cathepsin K (CTSK) is a member of the papain-like cysteine protease family. Mutations in the CTSK gene cause a rare autosomal recessive bone disorder called pycnodysostosis (OMIM 265800). In order to follow the advances in the research about CTSK and pycnodysostosis, we performed a literature retrospective study of 159 pycnodysostosis patients reported since 1996 and focused on the genetic characteristics of CTSK mutations and/or the clinical phenotypes of pycnodysostosis. Thirty three different CTSK mutations have been found in 59 unrelated pycnodysostosis families. Of the 59 families, 37.29% are from Europe and 30.51% are from Asia. A total of 69.70% of the mutations were identified in the mature domain of CTSK, 24.24% in the proregion, and 6.06% in the preregion. The hot mutation spots are found in exons 6 and 7. CTSK mutations result in total loss or inactivity of the CTSK protein, which causes abnormal degradation of bone matrix proteins such as type I collagen. Skeletal abnormalities, including short stature, an increase in bone density with pathologic fractures, and open fontanels and sutures, are the typical phenotypes of pycnodysostosis. Research on Ctsk(-/-) mouse models was also reviewed here to elucidate the biological function of Ctsk and the mechanism of pycnodysostosis. New evidence suggests that Ctsk plays an important role in the immune system and may serve as a valid therapeutic target in the future treatment of pycnodysostosis.