Dental Abnormalities Caused by Novel Compound Heterozygous CTSK Mutations.
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).
State Key Laboratory of Military Stomatology, Department of Oral Biology, Clinic of Oral Rare and Genetic Diseases, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, P. R. China.
Y
Y
Xue
Department of Molecular Biology, Fourth Military Medical University, Xi'an, Shaanxi, P. R. China.
L
L
Wang
Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Aarhus C, Denmark.
D
D
Xia
Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Aarhus C, Denmark.
Q
Q
Li
Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Aarhus C, Denmark.
S
S
Gao
Interdisciplinary Nanoscience Center (iNANO), Aarhus University, Aarhus C, Denmark.
M
M
Dong
Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
T
T
Cai
Center for Craniofacial Molecular Biology, University of Southern California School of Dentistry, Los Angeles, CA, USA.
S
S
Shi
State Key Laboratory of Military Stomatology, Department of Oral and Maxillofacial Surgery, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, P. R. China.
L
L
He
State Key Laboratory of Military Stomatology, Department of Oral and Maxillofacial Surgery, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, P. R. China.
K
K
Hu
State Key Laboratory of Military Stomatology, Department of Oral and Maxillofacial Surgery, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, P. R. China.
T
T
Mao
State Key Laboratory of Military Stomatology, Department of Oral Biology, Clinic of Oral Rare and Genetic Diseases, School of Stomatology, Fourth Military Medical University, Xi'an, Shaanxi, P. R. China xhduan@fmmu.edu.cn.
X
X
Duan
D000225:Adenine; D000328:Adult; D000483:Alleles; D000539:Alveolar Process / Q000002:abnormalities / Q000473:pathology; D000595:Amino Acid Sequence; D000818:Animals; D019556:COS Cells; D056657:Cathepsin K / Q000235:genetics*; D002522:Chlorocebus aethiops; D018388:Codon, Terminator / Q000235:genetics; D017124:Conserved Sequence / Q000235:genetics; D003545:Cysteine / Q000235:genetics; D003739:Dental Cementum / Q000002:abnormalities / Q000473:pathology; D006147:Guanine; D006579:Heterozygote; D006801:Humans; D008297:Male; D008957:Models, Genetic; D020125:Mutation, Missense / Q000235:genetics*; D010375:Pedigree; D019800:Phenol / Q000737:chemistry; D058631:Pycnodysostosis / Q000235:genetics / Q000473:pathology; D011862:Radiography, Panoramic / Q000379:methods; D014071:Tooth Abnormalities / Q000235:genetics* / Q000473:pathology; D014364:Tryptophan / Q000235:genetics; D014443:Tyrosine / Q000235:genetics; D055114:X-Ray Microtomography / Q000379:methods
D018388:Codon, Terminator; D019800:Phenol; D014443:Tyrosine; D006147:Guanine; D014364:Tryptophan; C534130:CTSK protein, human; D056657:Cathepsin K; D000225:Adenine; D003545:Cysteine
alveolar bone; cathepsin K; dental cementum; molecular biology; pycnodysostosis; tooth