Mutations within the gene encoding the alpha 1(X) chain of type X collagen (COL10A1) cause metaphyseal chondrodysplasia type Schmid but not several other forms of metaphyseal chondrodysplasia
Mutations within the gene encoding the alpha 1(X) chain of type X collagen (COL10A1) cause metaphyseal chondrodysplasia type Schmid but not several other forms of metaphyseal chondrodysplasia
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DOI：
10.1136/jmg.33.6.450
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发表时间：
1996-06-01
影响因子：
4
通讯作者：
BootHandford, RP
中科院分区：
文献类型：
--
作者：
Wallis, GA;Rash, B;BootHandford, RP
X型胶原蛋白是由COL10A1基因编码的α 1(X)链的同源三聚体。它是由软骨内成骨部位的肥大软骨细胞特异性地和短暂地合成的。编码α 1(X)羧基末端（NC1）结构域的COL10A1基因区域的点突变和缺失已经在干骺端软骨发育不良型施密德（MCDS）患者中被发现。为了确定该基因其他区域的突变是否会导致MCDS或类似的表型，我们使用PCR和SSCP分析了COL10A1基因的编码区和启动子区域，以及另外5名MCDS患者、1名非典型MCDS患者和9名其他形式的干骺端软骨发育不良患者的内含子/外显子边界。通过这种方法，我们发现3名MCDS患者在编码NC1结构域的COL10A1区域中存在1864delACTT、1956delT和2029delAC缺失的杂合性。这些缺失会导致阅读框的改变，过早终止密码子，以及截断蛋白产物的翻译。第四例MCDS患者的单碱基对T1894C是杂合的，这将导致NC1结构域中600位的氨基酸残基丝氨酸被脯氨酸取代。然而，我们没有在1名MCDS患者、1名非典型MCDS患者和9名其他形式的干骺端软骨发育不良患者中检测到COL10A1编码区和非编码区突变。我们提出，COL10A1 NC1结构域内导致MCDS的突变的性质和分布反驳了该表型仅通过单倍不足产生的假设，但迄今尚未解释的突变机制是该表型的基础。
Type X collagen is a homotrimer of alpha 1(X) chains encoded by the COL10A1 gene. It is synthesised specifically and transiently by hypertrophic chondrocytes at sites of endochondral ossification. Point mutations and deletions in the region of the COL10A1 gene encoding the alpha 1(X) carboxyl-terminal (NC1) domain have previously been identified in subjects with metaphyseal chondrodysplasia type Schmid (MCDS). To determine whether mutations in other regions of the gene caused MCDS or comparable phenotypes, we used PCR followed by SSCP to analyse the coding and promoter regions of the COL10A1 gene, as well as the intron/exon boundaries of five further subjects with MCDS, one subject with atypical MCDS, and nine subjects with other forms of metaphyseal chondrodysplasia. Using this approach, three of the subjects with MCDS were found to be heterozygous for the deletions 1864delACTT, 1956delT, and 2029delAC in the region of COL10A1 encoding the NC1 domain. These deletions would lead to alterations in the reading frame, premature stop codons, and the translation of truncated protein products. A fourth subject with MCDS was found to be heterozygous for a single base pair transition, T1894C, that would lead to the substitution of the amino acid residue serine at position 600 by proline within the NC1 domain. We did not, however, detect mutations in the coding and non-coding regions of COL10A1 in one subject with MCDS, the subject with atypical MCDS, and in the nine subjects with other forms of metaphyseal chondrodysplasia. We propose that the nature and distribution of mutations within the NC1 domain of COL10A1 causing MCDS argues against the hypothesis that the phenotype arises simply through haploinsufficiency but that an, as yet, unexplained mutation mechanism underlies this phenotype.