Mutations of CTSK result in pycnodysostosis via a reduction in cathepsin K protein

Nicola Ho, Antonello Punturieri, Douglas Wilkin, Jinny Szabo, Maureen Johnson, Justine Whaley, Joie Davis, Alison Clark, Stephen Weiss, Clair Francomano

Research output: Contribution to journalArticlepeer-review

46 Scopus citations


Pycnodyostosis, an autosomal recessive osteosclerosing skeletal disorder, has recently been shown to result from mutations in the cathepsin K gene. Cathepsin K, a lysosomal cysteine protease with an abundant expression in osteoclasts, has been implicated in osteoclast-mediated bone resorption and remodeling. DNA sequence analysis of the cathepsin K gene in a nonconsanguineous family demonstrated compound heterozygozity for mutations in two affected siblings. We have identified a missense mutation with a single base G→A transition at cDNA nucleotide 236, resulting in conversion of a conserved glycine to a glutamine residue (G79E). The other mutation is an A→T transition at nucleotide 154, leading to the substitution of a lysine residue by a STOP codon (K52X) predicting premature termination of the precursor cathepsin K polypeptide. Sequencing of genomic and cDNAs from the parents demonstrated that the missense mutation was inherited from the father and the nonsense mutation from the mother. Protein expression in both affected children was virtually absent, while in the parents was reduced by 50-80% compared with controls. The protein studies demonstrate that even significantly reduced cathepsin K levels do not have any phenotypic effect, whereas absent cathepsin K results in pycnodysostosis.

Original languageEnglish (US)
Pages (from-to)1649-1653
Number of pages5
JournalJournal of Bone and Mineral Research
Issue number10
StatePublished - 1999
Externally publishedYes

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine


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