Trinucleotide expansion mutations in the cartilage oligomeric matrix protein (COMP) gene
Trinucleotide expansion mutations in the cartilage oligomeric matrix protein (COMP) gene
复制标题
软骨寡聚基质蛋白（COMP）基因的三核苷酸扩增突变
DOI：
10.1093/hmg/8.1.123
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发表时间：
1999-01-01
影响因子：
3.5
通讯作者：
Cohn, DH
中科院分区：
文献类型：
--
作者：
Délot, E;King, LM;Cohn, DH
假性软骨发育不全（PSACH）和多发性骨骺发育不良（MED）是两种人类常染色体显性骨骼发育不良，其特征是可变身材矮小、关节松弛和早发性退行性关节疾病。这两种疾病都可能是由软骨寡聚基质蛋白（COMP）基因突变引起的，COMP是一种细胞外基质糖蛋白。大约三分之一的PSACH病例是由极短的三联体重复序列（GAC）中一个密码子缺失的杂合性引起的(5)，该序列编码COMP蛋白钙调素样区域内五个连续的天冬氨酸残基。我们在该重复序列中发现了两个扩增突变：MED患者携带GAC(6)等位基因，PSACH患者携带GAC(7)等位基因。这些是迄今为止所描述的最短的致病三联体重复扩增突变之一，并且是首次在GAC重复序列中发现的。该序列的一个独特特征是重复序列的扩增和缩短都可以引起相同的疾病。在软骨中，两例患者的软骨细胞中都有粗糙的内质网包涵体。这些内含物也存在于肌腱组织中，并可在培养的肌腱细胞中复制，这表明软骨和肌腱的疾病病理生理是相似的。
Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) are two human autosomal dominant skeletal dysplasias characterized by variable short stature, joint laxity and early-onset degenerative joint disease. Both disorders can result from mutations in the gene for cartilage oligomeric matrix protein (COMP), an extracellular matrix glycoprotein, About one-third of PSACH cases result from heterozygosity for deletion of one codon within a very short triplet repeat, (GAC)(5), which encodes five consecutive aspartic acid residues within the calmodulin-like region of the COMP protein. We have identified two expansion mutations in this repeat: an MED patient carrying a (GAC)(6) allele and a PSACH patient carrying a (GAC)(7) allele. These are among the shortest disease-causing triplet repeat expansion mutations described thus far, and are the first identified in a GAC repeat. A unique feature of this sequence is that expansion as well as shortening of the repeat can cause the same disease. In cartilage, both patients have rough endoplasmic reticulum inclusions in chondrocytes. The inclusions are also present in tendon tissue and can be reproduced in cultured tendon cells, suggesting that the pathophysiology of disease is similar in both cartilage and tendon.