Mutations of CTSK Result in Pycnodysostosis via a Reduction in Cathepsin K Protein

Abstract

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

The Regulation of Bone Resorption in Tooth Formation and Eruption Processes in Mouse Alveolar Crest Devoid of Cathepsin K

“…The morphology and abundance of TRAP-positive active osteoclasts seen in the alveolar bone surface around the tooth germ of CK-/ -mice were similar to those of the wild-type mice. The findings are not consistent with the previous finding that pycnodysostosis patients having mutation of the CK gene display abnormal craniofacial development and delayed eruption of dentition (14,33). Although long bones of CK-/ -mice revealed impaired bone resorption and closely resemble those described for pycnodysostosis patients, it has been reported that no overt phenotypic abnormalities were observed until the age of 10 months (16).…”

Cathepsin K gene mutations and 1q21 haplotypes in patients with pycnodysostosis in an outbred population

“…The second explanation would suggest the non-core haplotype chromosome in II:2 is much more distantly related than the other seven core-haplotype chromosomes. Our results confirm the disease locus previously reported [6][7][8][9][10][11] and show that at least three mutations exist in the Danish population. Consequently, this study indicates locus homogeneity and allele heterogeneity in pycnodysostosis within an outbred population.…”

“…8,9 Another seven mutations were described in nine unrelated families. 10,11 To focus on the question of locus heterogeneity and allele heterogeneity within the same population we here present a study of mutations and haplotypes in eight patients from five independent families with pycnodysostosis in an outbred Caucasian population.…”

An atypical subtrochanteric femoral fracture from pycnodysostosis: A lesson from nature

“…(2) Genetic linkage analysis of two kindreds assigned the locus for pycnodysostosis to chromosome 1q21, and missense, nonsense, and stop mutations involving the cathepsin K gene were found subsequently to cosegregate with the disease. (3)(4)(5) Cathepsin K is a lysosomal cysteine protease highly expressed in osteoclasts alone, thereby restricting the phenotype of pycnodysostosis to bone. (6) The treatment of pycnodysostosis is restricted to symptomatic management of fractures and other skeletal problems, but insights provided by identification of underlying gene mutations have led to the development of cathepsin K inhibitors for the treatment of osteoporosis.…”