Novel and recurrent COMP (cartilage oligomeric matrix protein) mutations in pseudoachondroplasia and multiple epiphyseal dysplasia
Novel and recurrent COMP (cartilage oligomeric matrix protein) mutations in pseudoachondroplasia and multiple epiphyseal dysplasia
复制标题
DOI：
10.1007/s004390050883
复制
发表时间：
1998-12-01
期刊：
影响因子：
5.3
通讯作者：
Nakamura, Y
中科院分区：
文献类型：
--
作者：
Ikegawa, S;Ohashi, H;Nakamura, Y
假性软骨发育不良(PSACH)和多发性骨骺发育不良(MED)是常见的骨发育不良，伴有软骨骨化受损和早期退行性关节疾病。这两种疾病过去被认为是不同的临床实体；然而，最近的研究证明，这两种疾病都可以由编码软骨寡聚基质蛋白(COMP)的基因突变引起。为了进一步确定CoMP突变的特征，并研究表型-基因型关系，我们对15名PSACH或MED患者的该基因进行了筛查，方法是直接对基因组DNA中的聚合酶链式反应产物进行测序。我们在该基因产物的8个类钙调素重复序列中发现了10个涉及保守残基的突变：7个是新发现的外显子9、10、11、13或14的错义突变，另外3个是由于外显子13的5个CAC重复序列中的一个缺失引起的。我们发现外显子13的第7个类钙调素重复序列中的GAC重复序列是突变的热点，第7个类钙调素重复序列的突变产生了严重的PSACH表型，而基因其他地方的突变表现为轻度的PSACH或MED表型。这些基因-表型相关性可能有助于PSACH和MED的分子诊断和分类，并有助于深入了解COMP基因产物的结构和功能之间的关系。
Pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED) are common skeletal dysplasias with impaired enchondral ossification and premature degenerative joint disease. The two disorders were in the past considered to be distinct clinical entities; however, recent studies have proven that both diseases can result from mutations of the gene encoding cartilage oligomeric matrix protein (COMP). To characterize further COMP mutations and investigate phenotype-genotype relationships, we screened this gene in 15 patients with PSACH or MED by directly sequencing polymerase chain reaction products from genomic DNA. We identified ten mutations involving conserved residues among the eight calmodulin-like repeats of the gene product: seven were novel missense mutations in exons 9, 10, 11, 13 or 14, and the other three resulted from deletion of one of the five CAC repeats in exon 13, We have found that the GAC repeats in the 7th calmodulin-like repeat in exon 13 represent a hot-spot for mutation, and that mutations in the 7th calmodulin-like repeat produce severe PSACH phenotypes while mutations elsewhere in the gene exhibit mild PSACH or MED phenotypes. These genotype-phenotype correlations may facilitate molecular diagnosis and classification of PSACH and MED, and provide insight into the relationship between structure and function of the COMP gene product.