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Novel Mutations of the Cathepsin K Gene in Patients with Pycnodysostosis and Their Characterization

Department of Orthopedic Surgery, Osaka University Medical School (Y.F., K.N., N.Y., E.K., T.O.), Suita City, Osaka 565-0871; the Department of Orthopedic Surgery, Osaka Medical Center for Maternal and Child Health (Y.M.), Izumi-City, Osaka 594-1101; the Department of Orthopedic Surgery, Osaka National Hospital (K.H.), Osaka City, Osaka 540-0006, and the Department of Orthopedic Surgery, Hyogo Nojigiku Medical Center for Disabled Children (R.S.), Kobe-City, Hyogo 651-2215, Japan

Address all correspondence and requests for reprints to: Dr. Yoshi Fujita, Department of Orthopedic Surgery, Osaka University Medical School, 2–2 Yamadaoka, Suita, Osaka 565-0871, Japan. E-mail: yfujita{at}ort.med.osaka-u.ac.jp

Pycnodysostosis is a rare autosomal recessive skeletal dysplasia characterized by short stature, osteosclerosis, acroosteolysis, bone fragility, and skull deformities. Recently, mutations in the gene encoding cathepsin K (CK), a lysosomal cysteine protease localized exclusively in osteoclasts, were found to be responsible for this disease. We analyzed genomic DNA from four unrelated Japanese patients with this disorder and identified three different mutations of their CK genes: a previously reported missense mutation (A277 V), a novel single base deletion mutation (531 del T) causing a frame shift from codon 142 that results in a premature termination codon, and a novel missense mutation (L9P) in the signal peptide region. To investigate whether the L9P mutation disrupts signal peptide function and decreases protein synthesis, mutant and wild-type CK complementary DNAs driven by the cytomegalovirus promoter were transfected into COS-7 cells, and their gene products were detected by immunohistochemistry and Western blotting. Expression of the mutant protein was markedly reduced, suggesting decreased mature CK production in this patient, which may have been due to dysfunction of the signal peptide. These results provide evidence that a structural change in the signal peptide of the CK protein was involved in the pathogenesis of pycnodysostosis.

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