A novel mutation (R122Q) in the cathepsin K gene in a Chinese child with Pyknodysostosis
Introduction
Pyknodysostosis (OMIM 265800) is a rare, autosomal recessive sclerosing skeletal dysplasia caused by cathepsin K deficiency. It was first described by Maroteaux and Lamy in 1962 (Maroteaux and Lamy, 1962), clinically characterized by osteosclerosis, short stature, acro-osteolysis of the distal phalanges, bone fragility, clavicular dysplasia, and skull deformities with delayed suture closure. Less than 200 cases have been reported worldwide, with an estimated prevalence to be 1 to 1.7 per million (Xue et al., 2011).
The gene encoding the phenotype was mapped to human chromosome 1q21 by genetic linkage analysis (Polymeropoulos et al., 1995), and ultimately was identified as cathepsin K (CTSK) in 1996 (Gelb et al., 1996). The CTSK gene spans approximately 12 kb and contains 8 exons (GenBank-EMBL no.NC_000001.8). The CTSK protein, a member of the papain-like cysteine protease family, is highly expressed in osteoclasts and it is believed to play a vital role in the resorption and remodeling of bone (Tezuka et al., 1994). Since 1996, 34 different CTSK mutations have been identified in 59 unrelated Pyknodysostosis families (Matsushita et al., 2012, Xue et al., 2011). However, only one mutation was identified in a Chinese patient (Li et al., 2009). Here in the present study, we have identified a novel homozygous missense mutation c.365G>A in exon 4 of the CTSK gene in a child with Pyknodysostosis in a non-consanguineous family of Tujia ethnicity in China.
Section snippets
Human subjects
This study was approved by the Ethics Committee of the Shanghai Jiao Tong University affiliated with the Sixth People's Hospital. All subjects involved in this study were recruited by the Department of Osteoporosis and Bone Diseases from outpatients. The pedigree of the family is shown in Fig. 1. The proband (II3) was an 11-year-old male; he was the third of three siblings in a non-consanguineous family of Tujia ethnicity. He was born with full term pregnancy and normal delivery. Birth weight
Results
No mutation of the CLCN7 gene was detected in the proband; we identified a novel missense mutation in the CTSK gene. DNA sequence analysis of all exons and exon–intron junctions showed the homozygous c.365G>A transition in exon 4 that resulted in the substitution of arginine at position 122 by glutamine (p.Arg122Gln) in the CTSK gene (Fig. 2). His parents were heterozygous for this p.Arg122Gln mutation. The mutation was not found in the 200 unrelated controls. In addition, by comparing the DNA
Discussion
Bone is undergoing a constant remodeling process that is balanced through the activities of bone-generating osteoblasts and bone-resorbing osteoclasts. The resorptive step includes mineral solubilization and focalized matrix degradation. Whereas mineral solubilization depends on the production and secretion of acid by the osteoclasts, matrix degradation is mainly due to the activity of the cysteine protease, cathepsin K (Bromme and Okamoto, 1995). In in vitro studies, cathepsin K can
Acknowledgments
The study was supported by the National Natural Science Foundation of China (81070692, 81000360, and 81170803), the Program of the Shanghai Subject Chief Scientist (08XD1403000), STCSM (10DZ1950100) and the Academic Leaders in Health Sciences in Shanghai (XBR2011014).
References (20)
Proteolytic activity of human osteoclast cathepsin K. Expression, purification, activation, and substrate identification
J. Biol. Chem.
(1996)Cleavage of type II collagen by cathepsin K in human osteoarthritic cartilage
Am. J. Pathol.
(2008)- et al.
Collagenase activity of cathepsin K depends on complex formation with chondroitin sulfate
J. Biol. Chem.
(2002) Molecular cloning of a possible cysteine proteinase predominantly expressed in osteoclasts
J. Biol. Chem.
(1994)Ablation of cathepsin K activity in the young mouse causes hypermineralization of long bone and growth plates
Calcif. Tissue Int.
(2009)- et al.
Human cathepsin O2, a novel cysteine protease highly expressed in osteoclastomas and ovary molecular cloning, sequencing and tissue distribution
Biol. Chem. Hoppe Seyler
(1995) - et al.
Cathepsin K: its skeletal actions and role as a therapeutic target in osteoporosis
Nat. Rev. Rheumatol.
(2011) - et al.
Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency
Science
(1996) - et al.
Human cathepsin K cleaves native type I and II collagens at the N-terminal end of the triple helix
Biochem. J.
(1998) - et al.
Molecular analysis of a novel cathepsin K gene mutation in a Chinese child with Pycnodysostosis
J. Int. Med. Res.
(2009)
Cited by (0)
- 1
The authors contributed equally to this work.