Identification of two novel COL10A1 heterozygous mutations in two Chinese pedigrees with Schmid-type metaphyseal chondrodysplasia
Identification of two novel COL10A1 heterozygous mutations in two Chinese pedigrees with Schmid-type metaphyseal chondrodysplasia
复制标题
两个 Schmid 型干骺端软骨发育不良家系中两个新的 COL10A1 杂合突变的鉴定
DOI：
10.1186/s12881-019-0937-1
复制
发表时间：
2019-12-19
影响因子：
--
通讯作者：
Kang, Qinglin
中科院分区：
文献类型：
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作者：
Kong, Lingchi;Shi, Li;Kang, Qinglin
背景
Schmid型干骺端软骨发育不良（MCDS）是由COL10A1突变引起的常染色体显性遗传性疾病，其特征是身材矮小、蹒跚步态、髋内翻和长骨弯曲。然而，对 MCDS 表达能力的描述却很少。
方法
两名先证者和可用的患有 MCDS 的家庭成员接受了临床和放射学检查。对所有受影响个体的基因组 DNA 进行了全外显子组测序，并通过桑格测序在所有可用的家庭成员和 250 名健康捐赠者中验证了候选突变。进一步构建了 X 型胶原 (α1) C 端非胶原 (NC1) 结构域的空间模型。
结果
我们发现受影响的家庭成员的表型表现出不完全显性。突变分析表明，家族1和家族2的COL10A1基因中分别存在两个新的杂合错义突变，[c.1765 T A (p.Phe589Ile)]和[c.1846AG (p.Lys616Glu)]。这两个新的取代位点高度保守，并且通过计算机分析预测这些突变是有害的。此外，蛋白质模型显示这两个取代位于胶原蛋白 X (α1) 的 NC1 结构域中，这可能影响胶原蛋白 X (α1) 的三聚化以及与细胞周基质中分子的结合。
结论
本研究发现了两个新的突变，这将有助于 MCDS 的诊断，并进一步扩大与 MCDS 患者相关的 COL10A1 突变谱。此外，我们的研究揭示了MCDS的不完全显性现象。
Background
Schmid-type metaphyseal chondrodysplasia (MCDS) is an autosomal dominant disorder caused by COL10A1 mutations, which is characterized by short stature, waddling gait, coxa vara and bowing of the long bones. However, descriptions of the expressivity of MCDS are rare.
Methods
Two probands and available family members affected with MCDS were subjected to clinical and radiological examination. Genomic DNA of all affected individuals was subjected to whole-exome sequencing, and candidate mutations were verified by Sanger sequencing in all available family members and in 250 healthy donors. A spatial model of the type X collagen (α1) C-terminal noncollagenous (NC1) domain was further constructed.
Results
We found that the phenotype of affected family members exhibited incomplete dominance. Mutation analysis indicated that there were two novel heterozygous missense mutations, [c.1765 T A (p.Phe589Ile)] and [c.1846A G (p.Lys616Glu)] in the COL10A1 gene in family 1 and 2, respectively. The two novel substitution sites were highly conserved and the mutations were predicted to be deleterious by in silico analysis. Furthermore, protein modeling revealed that the two substitutions were located in the NC1 domain of collagen X (α1), which potentially impacted the trimerization of collagen X (α1) and combination with molecules in the pericellular matrix.
Conclusion
Two novel mutations were identified in the present study, which will facilitate diagnosis of MCDS and further expand the spectrum of the COL10A1 mutations associated with MCDS patients. In addition, our research revealed the phenomenon of incomplete dominance in MCDS.