Metabolic Bone Disease and Genetic Research Unit, Department of Osteoporosis and Bone Diseases, Shanghai Jiao Tong University affiliated with the Sixth People's Hospital, 600 Yi-Shan Rd., Shanghai 200233, PR China.
Gene. 2013 May 25;521(1):176-9. doi: 10.1016/j.gene.2013.03.014. Epub 2013 Mar 16.
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.
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.
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.
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.
骨硬化性发育不良（OMIM 265800）是一种罕见的常染色体隐性硬化性骨骼发育不良，是破骨细胞降解有机骨基质能力下降的结果。骨硬化性发育不良是由组织蛋白酶 K（CTSK）基因突变引起的。迄今为止，在患有骨硬化性发育不良的患者中已经发现了 34 种不同的 CTSK 突变；然而，之前仅在一名中国患者中发现了一种突变。本研究的目的是描述骨硬化性发育不良的临床表现和特征，并鉴定一个中国骨硬化性发育不良家系中致病基因的突变。
我们调查了一个非近亲的中国家庭，其中一个 11 岁的孩子患有骨硬化性发育不良。共招募了包括受影响个体、其父母和 200 名健康供体在内的 203 人，并提取基因组 DNA。扩增并直接测序了 CTSK 基因的 8 个外显子，包括外显子-内含子边界。
先证者显示 CTSK 基因第 4 外显子中存在一个新的纯合错义突变 c.365G>A。该突变导致位于第 122 位的精氨酸被谷氨酰胺取代（R122Q）。父母对此基因突变均为杂合子，该突变在 200 名无关对照中未发现。
我们的研究表明，CTSK 基因第 4 外显子中的新型错义突变 c.365G>A（R122Q）是导致该中国家系骨硬化性发育不良的原因。
