Elsevier

Gene

Volume 521, Issue 1, 25 May 2013, Pages 176-179
Gene

A novel mutation (R122Q) in the cathepsin K gene in a Chinese child with Pyknodysostosis

https://doi.org/10.1016/j.gene.2013.03.014Get rights and content

Highlights

  • We characterized the clinical manifestations and features in a Chinese child with Pyknodysostosis.

  • A novel homozygous missense mutation c.365G>A (R122Q) in exon 4 of CTSK gene was identified.

  • This finding provides clues to the phenotype-genotype relations.

Abstract

Background

Pyknodysostosis (OMIM 265800) is a rare, autosomal recessive sclerosing skeletal dysplasia as a consequence of the diminished capacity of osteoclasts to degrade organic bone matrix. Pyknodysostosis is caused by mutation in the cathepsin K (CTSK) gene. Up to date, 34 different CTSK mutations have been identified in patients with Pyknodysostosis; however, only one mutation was previously identified in a Chinese patient. The objective of this study was to characterize the clinical manifestations and features of Pyknodysostosis and identify the mutation of the causative gene in a Chinese family with Pyknodysostosis.

Methods

We investigated a non-consanguineous Chinese family in which an 11-year-old child was affected with Pyknodysostosis. Altogether, 203 persons, including the affected individual, his parents and 200 healthy donors, were recruited and genomic DNA was extracted. All 8 exons of the CTSK gene, including the exon–intron boundaries, were amplified and sequenced directly.

Results

The proband displayed a novel homozygous missense mutation c.365G>A in exon 4 of the CTSK gene. This mutation leads to the substitution of the arginine at position 122 by glutamine (R122Q) in cathepsin K. The parents were heterozygous for this gene mutation, and the mutation was not found in the 200 unrelated controls.

Conclusion

Our study suggests that the novel missense mutation c.365G>A (R122Q) in exon 4 of CTSK gene was responsible for Pyknodysostosis in the Chinese family.

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).

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The authors contributed equally to this work.

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