A nonsense mutation in the cathepsin K gene observed in a family with pycnodysostosis
A nonsense mutation in the cathepsin K gene observed in a family with pycnodysostosis
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DOI：
10.1101/gr.6.11.1050
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发表时间：
1996-11-01
期刊：
影响因子：
7
通讯作者：
Francomano, CA
中科院分区：
文献类型：
--
作者：
Johnson, MR;Polymeropoulos, MH;Francomano, CA
密结性成骨不全症（MIM 265800）是一种罕见的常染色体隐性遗传性骨骼发育不良，其特征是身材矮小，颅缝宽，骨密度增加和脆性。连锁分析将致病基因定位于人类染色体1q21，随后将遗传间隔缩小到标记D1S2612和D1S2345之间。表达的序列标记的标志物对应于组织蛋白酶K，半胱氨酸蛋白酶高度表达在破骨细胞中，并认为是重要的骨吸收，以前被映射在候选区域。我们已经确定了一个大的，血缘关系的墨西哥家庭的受影响的个人的DNA中的组织蛋白酶K编码序列的核苷酸862（基因库登录号S79895）的胞嘧啶胸苷转换。该突变导致氨基酸241处的所有精氨酸变为STOP，预测组织蛋白酶K mRNA翻译的提前终止。该家系中所有受影响的个体均为该突变的纯合子，表明该改变可能导致密结性成骨不全。认识到组织蛋白酶K在致密骨发育不全病因学中的作用，将有助于了解其他骨重建疾病（包括骨质疏松症）的发病机制和治疗。
Pycnodysostosis (MIM 265800) is a rare, autosomal recessive skeletal dysplasia characterized by short stature, wide cranial sutures, and increased bone density and fragility. Linkage analysis localized the disease gene to human chromosome 1q21, and subsequently the genetic interval was narrowed to between markers D1S2612 and D1S2345. Expressed sequence tagged markers corresponding to cathepsin K, a cysteine protease highly expressed in osteoclasts and thought to be important in bone resorption, were mapped previously in the candidate region. We have identified a cytosine to thymidine transition at nucleotide 862 (GenBank accession no. S79895) of the cathepsin K coding sequence in the DNA of an affected individual from a large, consanguinous Mexican family. This mutation results in all arginine to STOP alteration at amino acid 241, predicting premature termination of cathepsin K mRNA translation. All affected individuals in this Family were homozygous for the mutation, suggesting that this alteration may lead to pycnodysostosis. Recognition of the role of cathepsin K in the etiology of pycnodysostosis should provide insights into the pathogenesis and treatment of other disorders of bone remodeling, including osteoporosis.