TY - JOUR
T1 - Mutations of CTSK result in pycnodysostosis via a reduction in cathepsin K protein
AU - Ho, Nicola
AU - Punturieri, Antonello
AU - Wilkin, Douglas
AU - Szabo, Jinny
AU - Johnson, Maureen
AU - Whaley, Justine
AU - Davis, Joie
AU - Clark, Alison
AU - Weiss, Stephen
AU - Francomano, Clair
PY - 1999
Y1 - 1999
N2 - 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.
AB - 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.
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U2 - 10.1359/jbmr.1999.14.10.1649
DO - 10.1359/jbmr.1999.14.10.1649
M3 - Article
C2 - 10491211
AN - SCOPUS:0032880960
SN - 0884-0431
VL - 14
SP - 1649
EP - 1653
JO - Journal of Bone and Mineral Research
JF - Journal of Bone and Mineral Research
IS - 10
ER -