Dental Abnormalities Caused by Novel Compound Heterozygous CTSK Mutations

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  • Y. Xue, China
  • L. Wang, Fourth Mil Med Univ, Fourth Military Medical University, Dept Mol Biol, China
  • D Xia, Aarhus Univ, Aarhus University, Interdisciplinary Nanosci Ctr iNANO
  • ,
  • Qiang Li
  • ,
  • Shan Gao
  • ,
  • MD Dong
  • T Cai, Natl Inst Dent & Craniofacial Res, NIH National Institute of Dental & Craniofacial Research (NIDCR), National Institutes of Health (NIH) - USA, Oral Infect & Immun Branch, NIH, United States
  • S Shi, Univ So Calif, University of Southern California, Ctr Craniofacial Mol Biol, Sch Dent, United States
  • L He, Fourth Mil Med Univ, Fourth Military Medical University, Sch Stomatol, Dept Oral & Maxillofacial Surg, State Key Lab Mil Stomatol, China
  • K. Hu, Fourth Mil Med Univ, Fourth Military Medical University, Sch Stomatol, Dept Oral & Maxillofacial Surg, State Key Lab Mil Stomatol
  • ,
  • T Mao, Fourth Mil Med Univ, Fourth Military Medical University, Sch Stomatol, Dept Oral & Maxillofacial Surg, State Key Lab Mil Stomatol, China
  • X Duan, Fourth Mil Med Univ, Fourth Military Medical University, Sch Stomatol, Clin Oral Rare & Genet Dis, State Key Lab Mil Stomatol,Dept Oral Biol, China

Cathepsin K (CTSK) is an important protease responsible for degrading type I collagen, osteopontin, and other bone matrix proteins. The mutations in the CTSK gene can cause pycnodysostosis (OMIM 265800), a rare autosomal recessive bone dysplasia. Patients with pycnodysostosis have been reported to present specific dental abnormalities; however, whether these dental abnormalities are related to dysfunctional CTSK has never been reported. Here we investigated the histologic changes of cementum and alveolar bone in a pycnodysostosis patient, caused by novel compound heterozygous mutations in the CTSK gene (c.87 G>A p.W29X and c.848 A>G p.Y283C). The most impressive manifestations in tooth were extensive periradicular high-density clumps with unclear periodontal space by orthopantomography examination and micro-computed tomography scanning analysis. Hematoxylin/eosin and toluidine blue staining and atomic force microscopy analysis showed that the cementum became significantly thickened, softened, and full of cementocytes. The disorganized bone structure was the main character of alveolar bone. The p.W29X mutation may represent the loss-of-function allele with an earlier termination codon in the precursor CTSK polypeptide. Residue Y283 is highly conserved among papain-like cysteine proteases. Three-dimensional structure modeling analysis found that the loss of the hydroxybenzene residue in the Y283C mutation would interrupt the hydrogen network and possibly affect the self-cleavage of the CTSK enzyme. Furthermore, p.Y283C mutation did not affect the mRNA and protein levels of overexpressed CTSK in COS-7 system but did reduce CTSK enzyme activity. In conclusion, the histologic and ultrastructural changes of cementum and alveolar bone might be affected by CTSK mutation via reduction of its enzyme activity (clinical trial registration: ChiCTR-TNC-10000876).

Original languageEnglish
JournalAdvances in Dental Research
Volume94
Issue5
Pages (from-to)674-681
Number of pages8
ISSN0022-0345
DOIs
Publication statusPublished - May 2015

    Research areas

  • pycnodysostosis, cathepsin K, molecular biology, tooth, dental cementum, alveolar bone, CATHEPSIN-K, PYCNODYSOSTOSIS, BONE, PYKNODYSOSTOSIS, ODONTOCLASTS, MICROSCOPY, RESORPTION, FEATURES, CEMENTUM, PATIENT

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